Ubiquitin specific peptidases and prostate cancer

Abstract

Protein ubiquitination is an important post-translational modification mechanism, which regulates protein stability and activity. The ubiquitination of proteins can be reversed by deubiquitinating enzymes (DUBs). Ubiquitin-specific proteases (USPs), the largest DUB subfamily, can regulate cellular functions by removing ubiquitin(s) from the target proteins. Prostate cancer (PCa) is the second leading type of cancer and the most common cause of cancer-related deaths in men worldwide. Numerous studies have demonstrated that the development of PCa is highly correlated with USPs. The expression of USPs is either high or low in PCa cells, thereby regulating the downstream signaling pathways and causing the development or suppression of PCa. This review summarized the functional roles of USPs in the development PCa and explored their potential applications as therapeutic targets for PCa.

Introduction

Regulation of gene expression is a complex process, involving interactions among DNA, RNA, proteins, and environment. The regulatory process of gene expression occurs at multiple levels to maintain the optimal levels of RNAs and proteins (Tran & Hutvagner, 2013). As an important regulatory mechanism, post-translational modifications (PTMs) are essential for cellular activities. There are several types of PTMs, such as phosphorylation, acetylation, methylation, sumoylation, and ubiquitination; each of them corresponds to one or more specific functions (Millar et al., 2019).

The ubiquitination of proteins plays a very important role in regulating protein function (Komander & Rape, 2012). It can regulate almost all aspects of cellular physiology (Hu et al., 2021). Ubiquitin, discovered in the 1980s (Cappadocia & Lima, 2018), is an 8.5-kDa small protein, containing 76 amino acids. This protein can be post-translationally attached to the substrate protein, usually at a lysine residue (Clague, Heride & Urbé, 2015; Rennie, Chaugule & Walden, 2020). As shown in Fig. 1, ubiquitin can covalently conjugate to the substrate proteins by three different enzymes, including E1, E2, and E3, during ubiquitination (Clague, Heride & Urbé, 2015). In eukaryotes, the ubiquitin-proteasome system, which is mainly composed of ubiquitin molecules, ubiquitylating enzymes, and 26S proteasomes, is an important pathway for the degradation of damaged or misfolded proteins (Chauhan et al., 2021; Svikle et al., 2022).

Figure 1: Ubiquitination/deubiquitination modifications and their regulatory role in protein degradation and cellular physiological functions. The process of ubiquitin (ub) binding to substrate proteins in the presence of E1, E2 and E3. This process is reversible and can remove ubiquitination modifications of substrate proteins in the presence of deubiquitinating enzymes (DUB). ubiquitination modifications at position K48 are proteins that undergo degradation to protein fragmentation via the 26S proteasome, while ubiquitination modifications at positions K6, K11, K27, K29, K33, K63 and M1 are involved in the regulation of numerous physiological processes in the cell. DOI: 10.7717/peerj.14799/fig-1

Ubiquitination is a covalent modification, which can be reversed by deubiquitinating enzymes (DUBs) (Bhoj & Chen, 2009; Chen, Liu & Zhou, 2021a). DUBs are proteases, which cleave peptide or isopeptide bonds between the two linked ubiquitin molecules or between ubiquitin and modified proteins (Clague, Urbé & Komander, 2019). It can reverse the E3 ubiquitin ligase-mediated protein modifications (Cheng et al., 2019b), thereby protecting proteins from degradation by the proteasomes (Haq, Suresh & Ramakrishna, 2018). Similar to ubiquitination, deubiquitination, catalyzed by DUBs, also plays a critical role in regulating cell functions (Schmidt et al., 2005; Daniel & Grant, 2007; Kennedy & D’Andrea, 2005; Lai, Chen & Tse, 2020; Ramakrishna, Suresh & Baek, 2011; Ramakrishna, Suresh & Baek, 2015). Recently, numerous DUBs have shown correlations with many diseases, such as cancer, inflammatory diseases, diabetes, and neurodegenerative diseases (Chen, Liu & Zhou, 2021a; Leznicki & Kulathu, 2017). The human genome encodes more than 100 DUBs, most of which are cysteine proteases (Leznicki & Kulathu, 2017). DUBs are divided into six families, including ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), ovarian tumor-related proteases (OTUs), Machado-Joseph disease protein domain proteases (MJDs), motif interacting with Ub-containing novel DUB family (MINDYs), and zinc finger-containing ubiquitin peptidase 1 (ZUP1) (Harrigan et al., 2018; Kwasna et al., 2018; Lei et al., 2021). USPs are the largest subfamily of DUBs, which are closely correlated with the development and progression of numerous cancer types, such as colorectal cancer (CRC) (Li et al., 2020), prostate cancer (PCa) (Liao et al., 2021a), liver cancer (Du et al., 2021), and breast cancer (Ma et al., 2019). Moreover, several USPs can also inhibit the occurrence and progression of cancer, such as glioblastoma (Kit Leng Lui et al., 2017).

PCa is the second leading type of cancer and the most common cause of cancer-related deaths in men worldwide (Vietri et al., 2021). The therapeutic strategies for PCa have been improved, albeit modestly, in the past few years, increasing the overall survival times of PCa patients (Nag & Dutta, 2020). PCa is highly dependent on androgen receptor (AR) signaling. AR is important for the growth and differentiation of normal prostate cells and plays a key role in the pathogenesis of PCa (Smolle et al., 2017). Therefore, androgen deprivation therapy (ADT) is the main treatment option for metastatic PCa (mPCa) (Sena & Denmeade, 2021; Tsujino et al., 2021). Despite its effectiveness, the patients receiving ADT can develop resistance, eventually developing castration-resistant PCa (CRPCa) (Fujita & Nonomura, 2019). Abiraterone and enzalutamide are second-generation ADTs, which are used for the treatment of CRPCa; however, cancer also eventually progresses to metastatic CRPCa (mCRPCa) (Berish et al., 2018). In addition to AR, the loss of tumor suppressors and aberrant activation or expression of oncogenes also play a crucial role in the progression of PCa. For example, the tumor suppressor genes p53 and PTEN and oncogene Myc are involved in the development and progression of PCa (Logothetis et al., 2013; Whitlock et al., 2020). In addition, numerous studies have also shown a strong correlation between the expression of DUBs and the progression of PCa (Deng et al., 2021; Ge et al., 2021; Jin et al., 2018; McClurg & Robson, 2015; Peng et al., 2022).

Ubiquitination and deubiquitination can regulate various aspects of human cell biology and physiology. The malfunction of these modifications can cause numerous diseases, including cancers. There has been a growing interest in exploiting the components of ubiquitination and deubiquitination machinery as therapeutic targets. Due to their greater numbers and diversity, DUBs are intrinsically attractive as potential drug targets. More than half of the total DUBs are USPs, which are cysteine peptidases. Currently, USPs have been extensively studied in various types of cancer. In terms of USPs’ role in PCa, Islam et al. (2019) showed that targeted ubiquitinase could regulate the therapeutic pathways of PCa. This review article summarized the expression patterns of different USPs in PCa and correlations between these expression patterns and the overall survival times of PCa patients as well as highlighted the mechanism of USPs, regulating the development and progression of PCa. This review article might provide basic knowledge for general readers as well as cancer researchers, especially those who are dedicated to PCa research and developing PCa drug targets.

Survey Methodology

PubMed database was used for related literature search using the keyword “USP,” “ubiquitin specific peptidase,” “ubiquitin-proteasome system,” “ubiquitination,” “deubiquitination,” “prostate cancer,” and “cancer.”

Structural characteristics of USPs

USPs were first discovered and cloned in Saccharomyces cerevisiae (Tobias & Varshavsky, 1991). They are the largest subfamily of DUBs having a total of 58 members. The number of USPs has increased since the evolution of E3 ubiquitin ligases (Semple, 2003). The size of USPs ranges from 330 amino acids to 3,500 amino acids with an average size of 800–1,000 amino acids for full-length enzymes. The catalytic structural domain of USPs contains 295-850 amino acids; the catalytic structural domain of 27 USPs contains 300–400 amino acids, while that of 29 USPs contains 400–850 amino acids (Ye et al., 2009). USPs have also other diverse domains in terms of size and structure (Hariri & St-Arnaud, 2021). However, there is a high degree of homology within the catalytic domain. The catalytic core of USPs contains three motifs, consisting of very conserved catalytic Cys residues, catalytic His residues, and catalytic Asp/Asn residues, which form the catalytic triad (Nijman et al., 2005; Ye et al., 2009). In addition to the catalytic domain, USPs also have domains for subcellular localization, substrate specificity, zinc binding, and ubiquitin recognition (Hariri & St-Arnaud, 2021; Nijman et al., 2005; Ye et al., 2009). Figure 2A shows USP4, USP7, USP14, USP19, and USP44 as examples of USPs having major domains.

Figure 2: The general domain structure of USP4, USP7, USP14, USP19 and USP44. (A) The DUSP (domain in USP) domain, UBL (ubiquitin-like) domain, TRAF (tumor necrosis factor receptor associated factor)-like domain, catalytic domain, CS (CHORD and SGT1) domain, ZnF-MYND (zinc-finger myeloid translocation protein 8, Nervy and Deaf1) domain and ZnF-UBP (zinc-finger ubiquitin binding) domain are represented by different colors and shapes. The numbers indicate the amino acid residues. As shown by the arrow, different USP domains bind to different substrate proteins. (B) The five UBL domains of USP7 make up the UBL unit. UBL4 and UBL5 interact with the catalytic domain of USP7 to activate USP7; Conversely, inactivation. DOI: 10.7717/peerj.14799/fig-2

The ubiquitin-like (UBL) domain of USPs can regulate their catalytic activity; however, the mechanism of action of the UBL domain in each USP varies. For example, the UBL domain of USP14 is important for its localization on proteasome and might enhance its catalytic capability., while that of USP4 binds to the catalytic domain, showing a competitive relationship with ubiquitin. As shown in Fig. 2B, the UBL4 and UBL5 domains of USP7 are located on its C-terminal and can affect its deubiquitinating activity by promoting conformational changes and facilitating the formation of a catalytic center (Faesen, Luna-Vargas & Sixma, 2012).

Different USPs have specific substrate proteins; therefore, they can regulate different signaling pathways (Ye et al., 2009). USPs can stabilize various oncoproteins or alter their cellular localization by deubiquitination, which can cause the development and progression of cancer (Chauhan et al., 2021). Numerous studies have shown that targeting USPs might be a promising therapeutic approach for cancer treatment (Dai et al., 2020; Du et al., 2021; Li et al., 2020; Ma et al., 2019; Nininahazwe et al., 2021; Zhu et al., 2020).

USPs and PCaUSP1

The mRNA expression levels of USP1 were higher in the PCa tissues as compared to those in the normal tissues. However, there were no differences in protein expression levels between PCa and normal tissues. USP1 could promote the proliferation of PCa cells, while the knockdown of the USP1 gene led to the inhibition of cellular proliferation (Liao et al., 2021a). Therefore, USP1 might play a promotional role in the development of PCa. Moreover, USP1 was highly expressed in cancer and was strongly correlated with the poor prognosis of patients with numerous cancer types, such as liver cancer, breast cancer, and multiple myeloma (Das et al., 2017; Liao et al., 2021b; Ma et al., 2019). These studies further supported USP1 as a potential target for cancer therapy. USP1 activity can be regulated by binding to UAF1 (USP1 associated factor 1), a protein, which contains a WD40 repeat sequence (Cohn et al., 2007). This binding significantly increases the enzymatic activity of USP1 (Cohn et al., 2007; García-Santisteban et al., 2013). The KDM4A (histone demethylase lysine-specific demethylase 4A) is upregulated in PCa, which is crucial for the survival and growth of PCa cells (Cui et al., 2020). USP1 can promote the growth and tumorigenesis of PCa cells by stabilizing the expression of KDM4A (Cui et al., 2020). The SIX1 (sine oculis homeobox homolog 1) is a poor prognostic indicator in PCa. USP1 can interact with SIX1 and stabilize its protein levels in a GRP75 (glucose regulated protein 75)-dependent manner, thereby promoting the cellular proliferation and castration resistance of PCa (Liao et al., 2021a; Liao et al., 2022).

USP2

USP2 is an oncoprotein overexpressed in PCa tissues (Priolo et al., 2006). USP2a is the largest isoform of USP2 (Renatus et al., 2006). Priolo et al. (2006) found that USP2a could protect the PCa cells from apoptosis, and its overexpression showed a tumorigenic effect in mice. In addition, the overexpression of USP2a can also enhance the proliferation and aggressiveness of PCa cells (Benassi et al., 2012). Studies have shown that the mRNA and protein expression levels of USP2a are upregulated in hepatocellular carcinoma (Xiong et al., 2021). USP2a can significantly promote the growth, invasion, and metastasis of liver cancer cells and is positively correlated with poor pathological grading, lymphatic metastasis, and poor prognosis (Xiong et al., 2021). Therefore, it can be speculated that USP2a might be a potentially effective target for cancer therapy. The upregulation of USP2 increases the levels of deubiquitinated substrates. For example, USP2 can stabilize the protein levels of FAS (fatty acid synthase), MDM2 (murine double minute 2), cyclin D1, and Aurora-A (Chuang et al., 2018). These proteins might play a critical role in the development and progression of PCa. Myc is an oncoprotein; its overexpression contributes to the development of PCa. USP2a can indirectly upregulate the expression of Myc to regulate the MDM2-p53-miR-34b/c axis by promoting the progression of cancer (Benassi et al., 2012; Benassi et al., 2013; Nelson, De Marzo & Yegnasubramanian, 2012). Fatty acid synthase (FAS) is overexpressed in prostate cancer, and it can protect the cancer cells from apoptosis (Graner et al., 2004). USP2a can promote the development of PCa by stabilizing FAS and preventing its proteasomal degradation. Seelan et al. suggested that USP2 could deubiquitinate acid ceramidase (ACDase) in the LNcap cell, and the protein expression levels of ACDase were highly correlated with USP2. Studies also showed that the mRNA and protein expression levels of ACDase were upregulated in the PCa cells (Seelan et al., 2000). The overexpression of ACDase could promote the proliferation of PCa cells in vitro and in vivo (Mizutani et al., 2015).

USP4

Studies have shown that USP4 has lower protein and mRNA expression levels in PCa tissues as compared to those in normal tissues (Chen et al., 2021b). Therefore, it can be speculated that USP4 might be a potentially effective target for the treatment of PCa. In PCa, METTL3 (methyltransferase like 3) is an upstream negative regulatory molecule of USP4. The upregulation of METT3 levels leads to the downregulation of USP4 levels, thereby reducing its deubiquitination ability, which causes a reduction in the levels of ELAVL1 (ELAV like RNA-binding protein 1). Consequently, the reduction in the ELAVL1 levels increases the expression levels of ARHGDIA (Rho GDP dissociation inhibitor α), which promotes the migration and invasion of PCa cells. It has been shown that the mRNA and protein expression levels of ARHGDIA are upregulated in PCa cells. In addition, the survival curve analysis showed a much shorter relapse-free survival of the PCa patients with higher ARHGDIA mRNA expression levels (Chen et al., 2021b). Therefore, it can be concluded that the invasion and metastasis of PCa cells can be inhibited by targeting and increasing the expression level of USP4.

USP7

USP7 is also known as herpesvirus-associated ubiquitin-specific protease (HAUSP) (Pozhidaeva et al., 2015). It has been overexpressed in PCa cells and is correlated with the invasion of their cells (Song et al., 2008). It can affect the migration, invasion, and sphere formation in PCa cells (Lee, Park & Kim, 2020). The knockdown of the USP7 gene can reduce the proliferation of PCa cells and induce their apoptosis (Shin et al., 2020). The PCa patients with high expression of USP7 had a worse prognosis in a large clinical population (Park et al., 2021). USP7 can interact with multiple substrate proteins, such as AR, FOXA1, FOXO4, PTEN, PLK1, MDM2, and CCDC6, to stabilize their protein levels (Chen et al., 2015; Morra et al., 2017; Park et al., 2021; Peng et al., 2019; Song et al., 2008; Van der Horst et al., 2006; Weinstock et al., 2012). USP7 is positively correlated with the PLK1 expression; both the USP7 and PLK1 have strong clinical relevance and are correlated with the poor prognosis of patients (Shin et al., 2020). The tissue expression levels of CCDC6 and USP7 can be used as markers to assess the treatment effects of advanced PCa, and their high expression predicts poor prognosis in patients with advanced PCa (Morra et al., 2017).

USP9X

USP9X, a conserved DUB, has a downregulated expression level in PCa tissues. The depletion of USP9X promotes the proliferation, migration, and invading abilities of PCa cells; these invasion and migration abilities are greater than the proliferation ability. Zhang et al. (2019) showed that the downregulation of the USP9X expression was correlated with poor differentiation and local invasion of PCa. This indicated that the PCa with low USP9X expression was highly deteriorated and had a negative impact on patients. USP9X can stabilize the levels of various protein substrates, such as PBX1, ERG, and IRS-2 (Furuta et al., 2018; Liu et al., 2019; Wang et al., 2016). PBX1 can promote the proliferation of PCa cells and is highly expressed in PCa. Studies have shown that the increased levels of PBX1 often lead to chemoresistance, which can be overcome in PCa patients by targeting the USP7-PBX1 axis (Liu et al., 2019). ERG is a major driver of PCa. Blocking the development of PCa by knocking down the USP9X leads to the ubiquitination and degradation of ERG protein (Wang et al., 2014).

USP10

The expression level of USP10 is upregulated in PCa tissues as compared to benign prostate tissues. USP10 can promote the proliferation of PCa cells and play an oncogenic role. The high expression of USP10 is correlated with the poor prognosis of patients. USP10 can deubiquitinate and stabilize the protein levels of G3BP2 (GTPase-activating protein-binding protein 2) and inhibit p53 activity to promote AR signaling pathway (Takayama et al., 2018). G3BP2 is upregulated in PCa and might serve as an independent prognostic marker for PCa patients (Ashikari et al., 2017).

USP12

USP12 is a novel biomarker for PCa. Its expression levels were upregulated in PCa and CRPCa. The upregulation of USP12 expression is correlated with the poor prognosis of PCa patients. McClurg et al. (2018b) found that the PCa patients with high expression levels of USP12 had significantly shorter overall survival and shorter recurrence time. USP12 is also closely associated with the levels of proliferation marker MCM2. Therefore, it can be inferred that USP12 can promote the proliferation of PCa cells. Mechanistically, USP12 can promote the development of PCa by stabilizing MDM2 protein levels and reducing p53 levels (McClurg et al., 2018b). USP12 is a novel regulator of AR by interacting with Uaf-1 and WDR20 to enzymatically perform the deubiquitination of AR, thereby enhancing its stability and transcriptional activity (Burska et al., 2013; McClurg et al., 2014). On the other hand, USP12 can also stabilize AR proteins and enhance their transcriptional activity by stabilizing the AKT (protein kinase B) dephosphorylases (PHLPP and PHLPPL) (McClurg et al., 2014). Stabilizing the AR protein and increasing its transcriptional activity can promote the proliferation and survival of PCa cells (Burska et al., 2013).

USP14

USP14 promotes the proliferation of PCa cells and is closely associated with its progression (Liao et al., 2017). It can also promote the development of PCa by stabilizing AR protein and ATF2 (activating the transcription factor 2) (Geng et al., 2020; Liao et al., 2017). USP14 is a novel regulator of AR (Liao et al., 2017). AR protein is overexpressed in PCa and plays a key role in its growth and progression (Liao et al., 2017). ATF2, an oncogene of PCa, facilitates the proliferation of PCa cells (Geng et al., 2020).

USP15

The Oncomine public data showed that the expression levels of USP15 were significantly elevated in PCa tissues, showing its potential clinical significance in PCa (Padmanabhan et al., 2018). Studies showed reported that USP15 was highly expressed in various malignancies, including gastric cancer. Moreover, the upregulation of USP15 expression was positively correlated with the clinical features of gastric cancer, such as tumor size, depth of invasion, lymph node involvement, tumor-node-metastasis stage, perineural invasion, and vascular invasion. USP15 is also strongly associated with poor prognosis of the patient and might be an oncogene in gastric cancer (Zhong et al., 2021). Notably, Fukushima et al. (2017) suggested that USP15 could inhibit the proliferation of the PCa cell line (PC-3). Mechanistically, USP15 inhibits the proliferation of PCa cells by antagonizing the NEDD4-induced ubiquitination of IRS-2, which leads to the reduction of tyrosine phosphorylation of IRS-2, resulting in a decreased IGF signaling (Fukushima et al., 2017). The IGF signaling pathway and increase in IGF levels contribute to the proliferation of PCa cells (Ahearn et al., 2018).

USP16

The expression level of USP16 is higher in PCa tissues as compared to those in the normal prostate tissues and is correlated with the poor prognosis of PCa patients. USP16 can promote the cellular proliferation and growth of PCa (Ge et al., 2021). c-Myc, an oncoprotein, is involved in cellular proliferation. USP16 can regulate the growth of PCa cells by stabilizing c-Myc (Ge et al., 2021).

USP17

USP17 has higher mRNA and protein levels in PCa tissues as compared to those in normal prostate tissues. The PCa patients with lower expression levels of USP17 have higher overall survival (Baohai, Shi & Yongqi, 2019). The knockdown of the USP17 gene can promote the production of ROS to induce apoptosis and decrease p65 phosphorylation, thereby inhibiting the proliferation, migration, and invasion of PCa cells as well as the progression of PCa (Baohai, Shi & Yongqi, 2019).

USP19

USP19 could regulate the growth of DU145, PC-3, and 22RV1 PCa cell lines but did not affect that of the LNCaP PCa cell line (Lu et al., 2011). The knockdown of the USP19 gene could inhibit the progression of PCa in two ways; first, by causing defects in cell cycle progression and delaying the progression from G0/G1 to S phase, and second, by accumulating p27^Kip1 and inhibiting the ability of USP19 to regulate cell growth (Lu et al., 2011).

USP22

USP22 has an important role in promoting malignant phenotypes by enhancing the stability of multiple cancer-associated protein targets through deubiquitination (Schrecengost et al., 2014). The mRNA and protein expression levels of USP22 are significantly upregulated in PCa. USP22 is a pro-oncogenic factor in PCa. Animal studies showed that USP22 conferred an excessive proliferation phenotype in vivo (McCann et al., 2020). USP22 is positively associated with the progression of PCa. Its upregulation not only shortens the survival times of patients but also correlates with the recurrence and poor prognosis of patients (Nag & Dutta, 2020). Therefore, USP22 can be used as a diagnostic biomarker. Mechanistically, USP22 promotes the progression of PCa by stabilizing the AR protein levels and regulating the AR-Myc signaling pathway (Schrecengost et al., 2014).

USP25

Although the clinical data showing the exact role of USP25 in PCa is currently lacking, USP25 expression is downregulated in PCa tissues as compared to normal tissues (Chen et al., 2021b). The wnt/β-catenin pathway is an important pathway for the development and progression of PCa (Cheng et al., 2019a). Tankyrase (TNKS) is a key mediator of the Wnt signaling pathway. USP25 can stabilize TNKS protein to promote the proliferation of PCa cells (Cheng et al., 2019a).

USP26

The expression level of USP26 is low in PCa tissues as compared to normal prostate tissues (Wosnitzer et al., 2014). A study reported that the mutations in the USP26 gene were not involved in the development of PCa, suggesting that the role of USP26 in the development of PCa might be due to changes in its protein expression levels (Dirac & Bernards, 2010). USP26 is an AR signaling regulator, which reverses AR ubiquitination, regulates the AR transcriptional activity, and protects the AR proteins from degradation (Dirac & Bernards, 2010). USP26 has a cancer promoter role due to its regulatory effects on AR.

USP33

The mRNA and protein expression levels of USP33, also known as VDU1, are upregulated in PCa (Ding et al., 2021; Guo et al., 2020). Guo et al. (2020) found that USP33 was an important tumor-promoting factor in PCa. It can inhibit apoptosis and enhance the cell survival of PCa cells. Current studies have shown that USP33 is an effective target for the treatment of PCa. USP33 promotes the development of PCa through two pathways. First, USP33 interacts with DUSP1 (dual-specificity phosphatase-1) to negatively regulate the JNK (cJUN NH2-terminal kinase) activation, thereby inhibiting the apoptosis of PCa cells (Guo et al., 2020). Second, PCa cells have upregulated levels of circ_ 0057558, which is a new biomarker for PCa and promotes cancer development by regulating the miR-206–USP33–c-Myc axis. Importantly, the expression levels of USP33 and circ _ 0057558 are positively correlated with PCa (Ding et al., 2021).

USP34

USP34 gene is correlated with the recurrence of PCa and is a predictive marker for its recurrence after radical prostatectomy. The high mRNA expression level of USP34 has a protective effect on the recurrence of PCa. Studies have shown that the Th2 (type 2 T helper) and Tcm (central memory T cell) immune cells are associated with the recurrence of PCa after radical prostatectomy and are the independent recurrence prevention factors. NDUFA13, UQCR11, and USP34 are involved in the infiltration of Th2 and Tcm cells in tumor tissues. The high expression of the USP34 can activate the Th2 and Tcm immune cells and recognize tumor cells through cellular and humoral immune effector mechanisms, thereby delaying the recurrence of PCa and improving prognosis. Conversely, the high expression levels of NDUFA13 and UQCR11 can inhibit tumor recognition by the human immune system, thereby significantly increasing the probability of tumor recurrence (Rui et al., 2019).

USP39

PCa cells, especially the AR-negative PCa cells have upregulated expression levels of USP39 (Huang et al., 2016). USP39 is a biomarker, which predicts poor prognosis and recurrence in patients. Studies have shown that USP39 can affect the colony formation of cancer cells and tumor growth. The inhibition of USP39 can induce G2/M phase arrest and promote apoptosis (Huang et al., 2016). USP39 is positively correlated with EGFR (epidermal growth factor receptor) levels; USP39 upregulates the mRNA and protein expression levels of EGFR (Huang et al., 2016). Studies have shown that EGFR is involved in the bone metastasis of PCa (Thoma, 2017). Therefore, inhibiting the EGFR signaling pathway might suppress the metastasis of PCa (Xiong et al., 2020). It is speculated that USP39 is a potential target for the treatment of PCa.

USP44

USP44 has a higher protein expression level in malignant and mPCa cells as compared to that in benign and weak mPCa cells (Park et al., 2019). USP44 can promote tumor formation and CSC (cancer stem cell) -like properties of PCa cells. USP44 could promote the invasive and migratory abilities of PCa cells in vitro, indicating its oncogenic behavior (Park et al., 2019). Mechanistically, USP44 can deubiquitinate to stabilize the EZH2 (enhancer of zeste homolog 2) protein levels and promote the development of PCa (Park et al., 2019). Moreover, EZH2 could facilitate the proliferation of PCa cells in vitro and in vivo. The overexpression of EZH2 is correlated with the deterioration of hormone-refractory mPCa. EZH2 is also a risk marker of the lethal progression of PCa (Varambally et al., 2002). Taken together, USP44 plays a role in the progression of PCa by regulating EZH2.

USP46

USP46 has highly similar to USP12 and has overlapping biological functions in PCa (McClurg et al., 2018a). The increased mRNA expression level of USP46 could predict a shorter relapse-free survival of patients. McClurg et al. (2018a) found that cancer development could be inhibited by targeting USP46. Moreover, USP46 can affect the progression of PCa by regulating the AR-AKT-MDM2-p53 signaling pathway (Li et al., 2013; McClurg et al., 2018a).

The correlations between USPs and PCa are summarized in Table 1.

Table 1: Ubiquitin-specific peptidases (USPs) related to prostate cancer.

USPs	Expression in prostate cancer	Pathways/Mechanism	Targets	Inhibitors	Reference
USP1	high expression (mRNA)	stabilization of KDM4A protein levels regulation of GRP75-SIX1 signaling axis	KDM4A SIX1	ML323 pimozide	Liao et al. (2021a); Ma et al. (2019); García-Santisteban et al. (2013); Cui et al. (2020)
USP2	high expression	regulation of MDM2-p53-Myc signaling axis stabilization of FAS protein levels stabilization of ACDase protein levels	MDM2 FAS ACDase	β-lapachone ML364	Priolo et al. (2006); Nelson, De Marzo & Yegnasubramanian (2012); Graner et al. (2004); Seelan et al. (2000); Gopinath et al. (2016); Zhang, Zhao & Sun (2021)
USP4	low expression	regulation of ELAVL1-ARHGDIA signaling axis	ELAVL1	Vialinin A	Chen et al. (2021b); Xu et al. (2021)
USP7	high expression	stabilization of PLK1 protein levels regulation of MDM2/MDMX-p53 signaling pathway regulation of AR signaling pathway regulation of localization of PTEN	PTEN AR KDM6A MDM2M DMX p53 PLK1	P5091 P22077 Almac4 HBX19818 GNE-6776 Quinazolin- 4(3H)-one HBX41108	Song et al. (2008); Shin et al. (2020); Peng et al. (2019); Chen et al. (2015); Li et al. (2002); Qi et al. (2020); Wang et al. (2021); Dai et al. (2020); Li et al. (2021); Tang et al. (2017)
USP9X	low expression	regulation of ERG signaling pathway regulation of MMP9-DRP1 signaling axis	ITCH ERG PBX1	WP1130 G9	Zhang et al. (2019); Lu et al. (2019); Pal et al. (2018)
USP10	high expression	regulation of AR singaling pathway	G3BP2	Spautin-1	Takayama et al. (2018); Liao et al. (2019)
USP12	high expression	regulation of AR signaling pathway regulation of TP53-MDM2-AR-AKT signaling axis regulation of AKT pathway	H2A H2B AR MDM2 PHLPPs	GW7647	McClurg et al. (2018b); McClurg et al. (2014)
USP14	unknown	stabilization of AR and MDM2 protein levels stabilization of ATF2 protein levels regulation of AR signaling	AR MDM2 ATF2	IU1 S5 b-AP15	Liao et al. (2017); Geng et al. (2020); Xu et al. (2020); Ming et al. (2021)
USP15	High expression (mRNA)	antagonizing the effect of NEDD4 to regulate IGF signaling pathway	Nedd4	Mitoxantrone USP15-Inh	Padmanabhan et al. (2018); Fukushima et al. (2017); Ward et al. (2018); Niederkorn et al. (2022)
USP16	high expression	stabilization of c-Myc protein levels	c-Myc	unknown	Ge et al. (2021)
USP17	high expression	regulation of EMT signaling pathway inhibition of USP17 can promote ROS production and inhibit NF-kB and p56	EMT	unknown	Baohai, Shi & Yongqi (2019)
USP19	unknown	regulation of p27 Kip1level	unknown	unknown	Lu et al. (2011)
USP22	high expression	regulation of AR and c-Myc dual signaling pathway	AR AR-v7 c-Myc	unknown	Schrecengost et al. (2014); McCann et al. (2020)
USP25	low expression (mRNA)	regulation of Wnt signaling pathway	TNKS	unknown	Chen et al. (2021b); Cheng et al. (2019a)
USP26	low Expression	regulation of AR signaling pathway	AR	unknown	Wosnitzer et al. (2014) Dirac & Bernards (2010)
USP33	high expression	regulation of DUSP1-JNK singaling axis stabilization of c-Myc protein levels	DUSP1 c-Myc	unknown	Guo et al. (2020) Ding et al. (2021)
USP39	high expression	regulation of EGFR signaling pathway	EGFR	unknown	Huang et al. (2016); Thoma (2017)
USP44	high expression	stabilization of EZH2 protein levels	EZH2	unknown	Park et al. (2019)
USP46	unknown	regulation of AR-AKT-MDM2-p53 signaling pathway stabilization of AR, MDM2 and PHLPPs protein levels	H2A H2B AR MDM2 PHLPPs	unknown	Li et al. (2013); McClurg et al. (2018a)

DOI: 10.7717/peerj.14799/table-1

Notes:

USPs

ubiquitin-specific peptidases

KDM4A

histone demethylase lysine-specific demethylase 4A

GRP75

glucose regulated protein 75

SIX1

sine oculis homeobox homolog 1

MDM2

murine double minute 2

FAS

fatty acid synthase

ACDase

acid ceramidase

KDM6A

histone demethylase lysine-specific demethylase 6A/UTX

MDMX

murine double minute X

AR

androgen receptor

ERG

ETS-related gene

MMP9

matrix metalloproteinase 9

DRP1

dynamin-related protein 1

PBX1

Pre-B cell leukemia homeobox-1

G3BP2

GTPase-activating protein-binding protein 2

ATF2

transcription factor 2

IGF

insulin growth factor

EMT

epithelial-mesenchymal transition

DUSP1

dual-specificity phosphatase-1

JNK

cJUN NH2-terminal kinase

EGFR

epidermal growth factor receptor

EZH2

enhancer of zeste homolog 2

Conclusions

Despite the developments in the treatment of PCa, there is an increasing need for new therapeutic targets. DUBs play an important role in the development of PCa and are promising drug targets. The development of small molecule inhibitors, targeting DUBs, holds great promise for the treatment of PCa. Some inhibitors have been applied in clinical practices, such as b-AP15, ML323, and Spautin-1. However, these studies are very limited and require further investigation. In addition, USPs are correlated with numerous cancer types. Thus, developing effective inhibitors against USPs are a promising method of finding new drugs for the treatment of cancers, including PCa. This review summarized the correlations between USPs and PCa. It was speculated that DUBs, especially USPs, might be effective therapeutic targets, provided that their molecular mechanism in PCa is extensively investigated. Therefore, to develop small molecule inhibitors against USPs for the clinical treatment of PCa and other cancers, more studies regarding the molecular mechanisms of USPs in various cancers and how these USPs themselves are regulated in future.

Additional Information and Declarations

Competing Interests

The authors declare there are no competing interests.

Author Contributions

Yunfei Guo performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Shuaishuai Cui analyzed the data, prepared figures and/or tables, and approved the final draft.

Yuanyuan Chen analyzed the data, prepared figures and/or tables, and approved the final draft.

Song Guo analyzed the data, prepared figures and/or tables, and approved the final draft.

Dahu Chen conceived and designed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Data Availability

The following information was supplied regarding data availability:

This literature review has no raw data or code.

Funding

This study was supported by the National Natural Science Foundation of China (81872005). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

Ahearn TU, Peisch S, Pettersson A, Ebot EM, Zhou CK, Graff RE, Sinnott JA, Fazli L, Judson GL, Bismar TA, Rider JR, Gerke T, Chan JM, Fiorentino M, Flavin R, Sesso HD, Finn S, Giovannucci EL, Gleave M, Loda M, Li Z, Pollak M, Mucci LA+13 more. 2018. Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease. Carcinogenesis 39:1431-1437

Ashikari D, Takayama K, Tanaka T, Suzuki Y, Obinata D, Fujimura T, Urano T, Takahashi S, Inoue S. 2017. Androgen induces G3BP2 and SUMO-mediated p53 nuclear export in prostate cancer. Oncogene 36:6272-6281

Baohai X, Shi F, Yongqi F. 2019. Inhibition of ubiquitin specific protease 17 restrains prostate cancer proliferation by regulation of epithelial-to-mesenchymal transition (EMT) via ROS production. Biomedicine and Pharmacotherapy 118:108946

Benassi B, Flavin R, Marchionni L, Zanata S, Pan Y, Chowdhury D, Marani M, Strano S, Muti P, Blandino G, Loda M+1 more. 2012. MYC is activated by USP2a-mediated modulation of microRNAs in prostate cancer. Cancer Discovery 2:236-247

Benassi B, Marani M, Loda M, Blandino G. 2013. USP2a alters chemotherapeutic response by modulating redox. Cell Death & Disease 4:e812

Berish RB, Ali AN, Telmer PG, Ronald JA, Leong HS. 2018. Translational models of prostate cancer bone metastasis. Nature Reviews Urology 15:403-421

Bhoj VG, Chen ZJ. 2009. Ubiquitylation in innate and adaptive immunity. Nature 458:430-437

Burska UL, Harle VJ, Coffey K, Darby S, Ramsey H, O’Neill D, Logan IR, Gaughan L, Robson CN. 2013. Deubiquitinating enzyme Usp12 is a novel co-activator of the androgen receptor. Journal of Biological Chemistry 288:32641-32650

Cappadocia L, Lima CD. 2018. Ubiquitin-like protein conjugation: structures, chemistry, and mechanism. Chemical Reviews 118:889-918

Chauhan R, Bhat AA, Masoodi T, Bagga P, Reddy R, Gupta A, Sheikh ZA, Macha MA, Haris M, Singh M. 2021. Ubiquitin-specific peptidase 37: an important cog in the oncogenic machinery of cancerous cells. Journal of Experimental & Clinical Cancer Research 40:356

Chen S, Liu Y, Zhou H. 2021a. Advances in the development ubiquitin-specific peptidase (USP) inhibitors. International Journal of Molecular Sciences 22:4546

Chen ST, Okada M, Nakato R, Izumi K, Bando M, Shirahige K. 2015. The deubiquitinating enzyme USP7 regulates androgen receptor activity by modulating its binding to chromatin. Journal of Biological Chemistry 290:21713-21723

Chen Y, Pan C, Wang X, Xu D, Ma Y, Hu J, Chen P, Xiang Z, Rao Q, Han X. 2021b. Silencing of METTL3 effectively hinders invasion and metastasis of prostate cancer cells. Theranostics 11:7640-7657

Cheng H, Li X, Wang C, Chen Y, Li S, Tan J, Tan B, He Y. 2019a. Inhibition of tankyrase by a novel small molecule significantly attenuates prostate cancer cell proliferation. Cancer Letters 443:80-90

Cheng J, Guo J, North BJ, Wang B, Cui CP, Li H, Tao K, Zhang L, Wei W. 2019b. Functional analysis of deubiquitylating enzymes in tumorigenesis and development. Biochimica et Biophysica Acta—Reviews on Cancer 1872:188312

Chuang SJ, Cheng SC, Tang HC, Sun CY, Chou CY. 2018. 6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2. Scientific Reports 8:3102

Clague MJ, Heride C, Urbé S. 2015. The demographics of the ubiquitin system. Trends in Cell Biology 25:417-426

Clague MJ, Urbé S, Komander D. 2019. Breaking the chains: deubiquitylating enzyme specificity begets function. Nature Reviews Molecular Cell Biology 20:338-352

Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D’Andrea AD. 2007. A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Molecular Cell 28:786-797

Cui SZ, Lei ZY, Guan TP, Fan LL, Li YQ, Geng XY, Fu DX, Jiang HW, Xu SH. 2020. Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy. Cancer Science 111:1567-1581

Dai X, Lu L, Deng S, Meng J, Wan C, Huang J, Sun Y, Hu Y, Wu B, Wu G, Lovell JF, Jin H, Yang K+3 more. 2020. USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer. Theranostics 10:9332-9347

Daniel JA, Grant PA. 2007. Multi-tasking on chromatin with the SAGA coactivator complexes. Mutation Research/DNA Repair 618:135-148

Das DS, Das A, Ray A, Song Y, Samur MK, Munshi NC, Chauhan D, Anderson KC. 2017. Blockade of deubiquitylating enzyme USP1 inhibits DNA repair and triggers apoptosis in multiple myeloma cells. Clinical Cancer Research 23:4280-4289

Deng R, Guo Y, Li L, He J, Qiang Z, Zhang H, Chen R, Wang Y, Zhao X, Yu J. 2021. BAP1 suppresses prostate cancer progression by deubiquitinating and stabilizing PTEN. Molecular Oncology 15:279-298

Ding T, Zhu Y, Jin H, Zhang P, Guo J, Zheng J. 2021. Circular RNA circ_0057558 controls prostate cancer cell proliferation through regulating miR-206/USP33/c-Myc axis. Frontiers in Cell and Developmental Biology 9:644397

Dirac AM, Bernards R. 2010. The deubiquitinating enzyme USP26 is a regulator of androgen receptor signaling. Molecular Cancer Research 8:844-854

Du L, Li Y, Kang M, Feng M, Ren Y, Dai H, Wang Y, Wang Y, Tang B. 2021. USP48 is upregulated by mettl14 to attenuate hepatocellular carcinoma via regulating SIRT6 stabilization. Cancer Research 81:3822-3834

Faesen AC, Luna-Vargas MP, Sixma TK. 2012. The role of UBL domains in ubiquitin-specific proteases. Biochemical Society Transactions 40:539-545

Fujita K, Nonomura N. 2019. Role of androgen receptor in prostate cancer: a review. The World Journal of Men’s Health 37:288-295

Fukushima T, Yoshihara H, Furuta H, Hakuno F, Iemura SI, Natsume T, Nakatsu Y, Kamata H, Asano T, Komada M, Takahashi SI+1 more. 2017. USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination. Biochemical and Biophysical Research Communications 484:522-528

Furuta H, Yoshihara H, Fukushima T, Yoneyama Y, Ito A, Worrall C, Girnita A, Girnita L, Yoshida M, Asano T, Komada M, Kataoka N, Chida K, Hakuno F, Takahashi SI+5 more. 2018. IRS-2 deubiquitination by USP9X maintains anchorage-independent cell growth via Erk1/2 activation in prostate carcinoma cell line. Oncotarget 9:33871-33883

García-Santisteban I, Peters GJ, Giovannetti E, Rodríguez JA. 2013. USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy. Molecular Cancer 12:91

Ge J, Yu W, Li J, Ma H, Wang P, Zhou Y, Wang Y, Zhang J, Shi G. 2021. USP16 regulates castration-resistant prostate cancer cell proliferation by deubiquitinating and stablizing c-Myc. Journal of Experimental & Clinical Cancer Research 40:59

Geng L, Chen X, Zhang M, Luo Z. 2020. Ubiquitin-specific protease 14 promotes prostate cancer progression through deubiquitinating the transcriptional factor ATF2. Biochemical and Biophysical Research Communications 524:16-21

Gopinath P, Mahammed A, Ohayon S, Gross Z, Brik A. 2016. Understanding and predicting the potency of ROS-based enzyme inhibitors, exemplified by naphthoquinones and ubiquitin specific protease-2. Chemical Science 7:7079-7086

Graner E, Tang D, Rossi S, Baron A, Migita T, Weinstein LJ, Lechpammer M, Huesken D, Zimmermann J, Signoretti S, Loda M+1 more. 2004. The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell 5:253-261

Guo F, Zhang C, Wang F, Zhang W, Shi X, Zhu Y, Fang Z, Yang B, Sun Y. 2020. Deubiquitinating enzyme USP33 restrains docetaxel-induced apoptosis via stabilising the phosphatase DUSP1 in prostate cancer. Cell Death and Differentiation 27:1938-1951

Haq S, Suresh B, Ramakrishna S. 2018. Deubiquitylating enzymes as cancer stem cell therapeutics. Biochimica et Biophysica Acta—Reviews on Cancer 1869:1-10

Hariri H, St-Arnaud R. 2021. Expression and role of ubiquitin-specific peptidases in osteoblasts. International Journal of Molecular Sciences 22:7746

Harrigan JA, Jacq X, Martin NM, Jackson SP. 2018. Deubiquitylating enzymes and drug discovery: emerging opportunities. Nature Reviews Drug Discovery 17:57-78

Hu Z, Li H, Wang X, Ullah K, Xu G. 2021. Proteomic approaches for the profiling of ubiquitylation events and their applications in drug discovery. Journal of Proteomics 231:103996

Huang Y, Pan XW, Li L, Chen L, Liu X, Lu JL, Zhu XM, Huang H, Yang QW, Ye JQ, Gan SS, Wang LH, Hong Y, Xu DF, Cui XG+5 more. 2016. Overexpression of USP39 predicts poor prognosis and promotes tumorigenesis of prostate cancer via promoting EGFR mRNA maturation and transcription elongation. Oncotarget 7:22016-22030

Islam MT, Zhou X, Chen F, Khan MA, Fu J, Chen H. 2019. Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics. Cell Biochemistry and Function 37:304-319

Jin X, Yan Y, Wang D, Ding D, Ma T, Ye Z, Jimenez R, Wang L, Wu H, Huang H. 2018. DUB3 promotes BET inhibitor resistance and cancer progression by deubiquitinating BRD4. Molecular Cell 71:592-605

Kennedy RD, D’Andrea AD. 2005. The fanconi anemia/BRCA pathway: new faces in the crowd. Genes and Development 19:2925-2940

Kit Leng Lui S, Iyengar PV, Jaynes P, Isa Z, Pang B, Tan TZ, Eichhorn PJA. 2017. USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7. EMBO Reports 18:797-808

Komander D, Rape M. 2012. The ubiquitin code. Annual Review of Biochemistry 81:203-229

Kwasna D, Abdul Rehman SA, Natarajan J, Matthews S, Madden R, De Cesare V, Weidlich S, Virdee S, Ahel I, Gibbs-Seymour I, Kulathu Y+1 more. 2018. Discovery and characterization of ZUFSP/ZUP1, a distinct deubiquitinase class important for genome stability. Molecular Cell 70:150-164

Lai KP, Chen J, Tse WKF. 2020. Role of deubiquitinases in human cancers: potential targeted therapy. International Journal of Molecular Sciences 21:2548

Lee JE, Park CM, Kim JH. 2020. USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells. Genetics and Molecular Biology 43:e20190338

Lei H, Wang J, Hu J, Zhu Q, Wu Y. 2021. Deubiquitinases in hematological malignancies. Biomarker Research 9:66

Leznicki P, Kulathu Y. 2017. Mechanisms of regulation and diversification of deubiquitylating enzyme function. Journal of Cell Science 130:1997-2006

Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W. 2002. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416:648-653

Li P, Liu Y, Yang H, Liu HM. 2021. Design, synthesis, biological evaluation and structure–activity relationship study of quinazolin-4(3H)-one derivatives as novel USP7 inhibitors. European Journal of Medicinal Chemistry 216:113291

Li X, Kong L, Yang Q, Duan A, Ju X, Cai B, Chen L, An T, Li Y. 2020. Parthenolide inhibits ubiquitin-specific peptidase 7 (USP7), Wnt signaling, and colorectal cancer cell growth. Journal of Biological Chemistry 295:3576-3589

Li X, Stevens PD, Yang H, Gulhati P, Wang W, Evers BM, Gao T. 2013. The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer. Oncogene 32:471-478

Liao Y, Guo Z, Xia X, Liu Y, Huang C, Jiang L, Wang X, Liu J, Huang H. 2019. Inhibition of EGFR signaling with Spautin-1 represents a novel therapeutics for prostate cancer. Journal of Experimental & Clinical Cancer Research 38:157

Liao Y, Liu N, Hua X, Cai J, Xia X, Wang X, Huang H, Liu J. 2017. Proteasome-associated deubiquitinase ubiquitin-specific protease 14 regulates prostate cancer proliferation by deubiquitinating and stabilizing androgen receptor. Cell Death & Disease 8:e2585

Liao Y, Liu Y, Shao Z, Xia X, Deng Y, Cai J, Yao L, He J, Yu C, Hu T, Sun W, Liu F, Tang D, Liu J, Huang H+5 more. 2021a. A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance. Oncogene 40:4291-4306

Liao Y, Shao Z, Liu Y, Xia X, Deng Y, Yu C, Sun W, Kong W, He X, Liu F, Guo Z, Chen G, Tang D, Gan H, Liu J, Huang H+6 more. 2021b. USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells. Journal of Experimental & Clinical Cancer Research 40:201

Liao Y, Sun W, Shao Z, Liu Y, Zhong X, Deng Y, Liu F, Huang H, Liu J. 2022. A SIX1 degradation inducer blocks excessive proliferation of prostate cancer. International Journal of Biological Sciences 18:2439-2451

Liu Y, Xu X, Lin P, He Y, Zhang Y, Cao B, Zhang Z, Sethi G, Liu J, Zhou X, Mao X+1 more. 2019. Inhibition of the deubiquitinase USP9x induces pre-B cell homeobox 1 (PBX1) degradation and thereby stimulates prostate cancer cell apoptosis. Journal of Biological Chemistry 294:4572-4582

Logothetis CJ, Gallick GE, Maity SN, Kim J, Aparicio A, Efstathiou E, Lin SH. 2013. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer. Cancer Discovery 3:849-861

Lu Q, Zhang FL, Lu DY, Shao ZM, Li DQ. 2019. USP9X stabilizes BRCA1 and confers resistance to DNA-damaging agents in human cancer cells. Cancer Medicine 8:6730-6740

Lu Y, Bedard N, Chevalier S, Wing SS. 2011. Identification of distinctive patterns of USP19-mediated growth regulation in normal and malignant cells. PLOS ONE 6:e15936

Ma A, Tang M, Zhang L, Wang B, Yang Z, Liu Y, Xu G, Wu L, Jing T, Xu X, Yang S, Liu Y+2 more. 2019. USP1 inhibition destabilizes KPNA2 and suppresses breast cancer metastasis. Oncogene 38:2405-2419

McCann JJ, Vasilevskaya IA, Poudel Neupane N, Shafi AA, McNair C, Dylgjeri E, Mandigo AC, Schiewer MJ, Schrecengost RS, Gallagher P, Stanek TJ, McMahon SB, Berman-Booty LD, Ostrander Jr WF, Knudsen KE+5 more. 2020. USP22 Functions as an oncogenic driver in prostate cancer by regulating cell proliferation and DNA repair. Cancer Research 80:430-443

McClurg UL, Azizyan M, Dransfield DT, Namdev N, Chit N, Nakjang S, Robson CN. 2018a. The novel anti-androgen candidate galeterone targets deubiquitinating enzymes, USP12 and USP46, to control prostate cancer growth and survival. Oncotarget 9:24992-25007

McClurg UL, Chit N, Azizyan M, Edwards J, Nabbi A, Riabowol KT, Nakjang S, McCracken SR, Robson CN. 2018b. Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12. Oncogene 37:4679-4691

McClurg UL, Robson CN. 2015. Deubiquitinating enzymes as oncotargets. Oncotarget 6:9657-9668

McClurg UL, Summerscales EE, Harle VJ, Gaughan L, Robson CN. 2014. Deubiquitinating enzyme Usp12 regulates the interaction between the androgen receptor and the Akt pathway. Oncotarget 5:7081-7092

Millar AH, Heazlewood JL, Giglione C, Holdsworth MJ, Bachmair A, Schulze WX. 2019. The scope, functions, and dynamics of posttranslational protein modifications. Annual Review of Plant Biology 70:119-151

Ming SL, Zhang S, Wang Q, Zeng L, Zhou LY, Wang MD, Ma YX, Han LQ, Zhong K, Zhu HS, Bai YL, Yang GY, Wang J, Chu BB+4 more. 2021. Inhibition of USP14 influences alphaherpesvirus proliferation by degrading viral VP16 protein via ER stress-triggered selective autophagy. Autophagy 18:1801-1821

Mizutani N, Inoue M, Omori Y, Ito H, Tamiya-Koizumi K, Takagi A, Kojima T, Nakamura M, Iwaki S, Nakatochi M, Suzuki M, Nozawa Y, Murate T+3 more. 2015. Increased acid ceramidase expression depends on upregulation of androgen-dependent deubiquitinases, USP2, in a human prostate cancer cell line, LNCaP. Journal of Biochemistry 158:309-319

Morra F, Merolla F, Napolitano V, Ilardi G, Miro C, Paladino S, Staibano S, Cerrato A, Celetti A. 2017. The combined effect of USP7 inhibitors and PARP inhibitors in hormone-sensitive and castration-resistant prostate cancer cells. Oncotarget 8:31815-31829

Nag N, Dutta S. 2020. Deubiquitination in prostate cancer progression: role of USP22. Journal of Cancer Metastasis and Treatment 6:16

Nelson WG, De Marzo AM, Yegnasubramanian S. 2012. USP2a activation of MYC in prostate cancer. Cancer Discovery 2:206-207

Niederkorn M, Ishikawa C, MH K, Bartram J, Stepanchick E, RB J, EC-C A, Bolanos LC, Uible E, Choi K, Wunderlich M, Perentesis JP, MC T, Filippi MD, Starczynowski DT+5 more. 2022. The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia. Leukemia 36:438-451

Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R. 2005. A genomic and functional inventory of deubiquitinating enzymes. Cell 123:773-786

Nininahazwe L, Liu B, He C, Zhang H, Chen ZS. 2021. The emerging nature of Ubiquitin-specific protease 7 (USP7): a new target in cancer therapy. Drug Discovery Today 26:490-502

Padmanabhan A, Candelaria N, Wong KK, Nikolai BC, Lonard DM, O’Malley BW, Richards JS. 2018. USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells. Nature Communications 9:1270

Pal A, Dziubinski M, Di Magliano MP, Simeone DM, Owens S, Thomas D, Peterson L, Potu H, Talpaz M, Donato NJ. 2018. Usp9x promotes survival in human pancreatic cancer and its inhibition suppresses pancreatic ductal adenocarcinoma in vivo tumor growth. Neoplasia 20:152-164

Park JM, Lee JE, Park CM, Kim JH. 2019. USP44 promotes the tumorigenesis of prostate cancer cells through EZH2 protein stabilization. Molecular Cell 42:17-27

Park SH, Fong KW, Kim J, Wang F, Lu X, Lee Y, Brea LT, Wadosky K, Guo C, Abdulkadir SA, Crispino JD, Fang D, Ntziachristos P, Liu X, Li X, Wan Y, Goodrich DW, Zhao JC, Yu J+9 more. 2021. Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer. Science Advances 7:eabe2261

Peng Y, Liu J, Wang Z, Cui C, Zhang T, Zhang S, Gao P, Hou Z, Liu H, Guo J, Zhang J, Wen Y, Wei W, Zhang L, Liu J, Long J+6 more. 2022. Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc. Cell Death and Differentiation 29:1730-1743

Peng Y, Liu Y, Gao Y, Yuan B, Qi X, Fu Y, Zhu Q, Cao T, Zhang S, Yin L, Li X+1 more. 2019. USP7 is a novel Deubiquitinase sustaining PLK1 protein stability and regulating chromosome alignment in mitosis. Journal of Experimental & Clinical Cancer Research 38:468

Pozhidaeva AK, Mohni KN, Dhe-Paganon S, Arrowsmith CH, Weller SK, Korzhnev DM, Bezsonova I. 2015. Structural characterization of interaction between human ubiquitin-specific protease 7 and immediate-early protein ICP0 of herpes simplex virus-1. Journal of Biological Chemistry 290:22907-22918

Priolo C, Tang D, Brahamandan M, Benassi B, Sicinska E, Ogino S, Farsetti A, Porrello A, Finn S, Zimmermann J, Febbo P, Loda M+2 more. 2006. The isopeptidase USP2a protects human prostate cancer from apoptosis. Cancer Research 66:8625-8632

Qi SM, Cheng G, Cheng XD, Xu Z, Xu B, Zhang WD, Qin JJ. 2020. Targeting USP7-mediated deubiquitination of MDM2/MDMX-p53 pathway for cancer therapy: are we there yet? Frontiers in Cell and Developmental Biology 8:233

Ramakrishna S, Suresh B, Baek KH. 2011. The role of deubiquitinating enzymes in apoptosis. Cellular and Molecular Life Science 68:15-26

Ramakrishna S, Suresh B, Baek KH. 2015. Biological functions of hyaluronan and cytokine-inducible deubiquitinating enzymes. Biochimica Et Biophysica Acta/General Subjects 1855:83-91

Renatus M, Parrado SG, D’Arcy A, Eidhoff U, Gerhartz B, Hassiepen U, Pierrat B, Riedl R, Vinzenz D, Worpenberg S, Kroemer M+1 more. 2006. Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. Structure 14:1293-1302

Rennie ML, Chaugule VK, Walden H. 2020. Modes of allosteric regulation of the ubiquitination machinery. Current Opinion in Structural Biology 62:189-196

Rui X, Shao S, Wang L, Leng J. 2019. Identification of recurrence marker associated with immune infiltration in prostate cancer with radical resection and build prognostic nomogram. BMC Cancer 19:1179

Schmidt M, Hanna J, Elsasser S, Finley D. 2005. Proteasome-associated proteins: regulation of a proteolytic machine. Biological Chemistry 386:725-737

Schrecengost RS, Dean JL, Goodwin JF, Schiewer MJ, Urban MW, Stanek TJ, Sussman RT, Hicks JL, Birbe RC, Draganova-Tacheva RA, Visakorpi T, De Marzo AM, McMahon SB, Knudsen KE+4 more. 2014. USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer Research 74:272-286

Seelan RS, Qian C, Yokomizo A, Bostwick DG, Smith DI, Liu W. 2000. Human acid ceramidase is overexpressed but not mutated in prostate cancer. Genes Chromosomes Cancer 29:137-146

Semple CA. 2003. The comparative proteomics of ubiquitination in mouse. Genome Research 13:1389-1394

Sena LA, Denmeade SR. 2021. Fatty acid synthesis in prostate cancer: vulnerability or epiphenomenon? Cancer Research 81:4385-4393

Shin SB, Kim CH, Jang HR, Yim H. 2020. Combination of inhibitors of USP7 and PLK1 has a strong synergism against paclitaxel resistance. International Journal of Molecular Sciences 21:8629

Smolle MA, Bauernhofer T, Pummer K, Calin GA, Pichler M. 2017. Current insights into long non-coding RNAs (LncRNAs) in prostate cancer. International Journal of Molecular Sciences 18:473

Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP. 2008. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 455:813-817

Svikle Z, Peterfelde B, Sjakste N, Baumane K, Verkauskiene R, Jeng CJ, Sokolovska J. 2022. Ubiquitin-proteasome system in diabetic retinopathy. PeerJ 10:e13715

Takayama KI, Suzuki T, Fujimura T, Takahashi S, Inoue S. 2018. Association of USP10 with G3BP2 inhibits p53 signaling and contributes to poor outcome in prostate cancer. Molecular Cancer Research 16:846-856

Tang Y, Lv L, Li W, Zhang X, Jiang Y, Ge W, Zhou Y. 2017. Protein deubiquitinase USP7 is required for osteogenic differentiation of human adipose-derived stem cells. Stem Cell Research & Therapy 8:186

Thoma C. 2017. Prostate cancer: role for EGFR & HER2 in bone metastasis. Nature Reviews Urology 14:7

Tobias JW, Varshavsky A. 1991. Cloning and functional analysis of the ubiquitin-specific protease gene UBP1 of Saccharomyces cerevisiae. Journal of Biological Chemistry 266:12021-12028

Tran N, Hutvagner G. 2013. Biogenesis and the regulation of the maturation of miRNAs. Essays in Biochemistry 54:17-28

Tsujino T, Komura K, Inamoto T, Azuma H. 2021. CRISPR screen contributes to novel target discovery in prostate cancer. International Journal of Molecular Sciences 22:12777

Van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burgering BM. 2006. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature Cell Biology 8:1064-1073

Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM+2 more. 2002. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624-629

Vietri MT, D’Elia G, Caliendo G, Resse M, Casamassimi A, Passariello L, Albanese L, Cioffi M, Molinari AM. 2021. Hereditary prostate cancer: genes related, target therapy and prevention. International Journal of Molecular Sciences 22:3753

Wang S, Kollipara RK, Humphries CG, Ma SH, Hutchinson R, Li R, Siddiqui J, Tomlins SA, Raj GV, Kittler R. 2016. The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer. Oncotarget 7:64921-64931

Wang S, Kollipara RK, Srivastava N, Li R, Ravindranathan P, Hernandez E, Freeman E, Humphries CG, Kapur P, Lotan Y, Fazli L, Gleave ME, Plymate SR, Raj GV, Hsieh JT, Kittler R+6 more. 2014. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 111:4251-4256

Wang Z, Kang W, Li O, Qi F, Wang J, You Y, He P, Suo Z, Zheng Y, Liu HM. 2021. Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing. Acta Pharmaceutica Sinica B 11:694-707

Ward SJ, Gratton HE, Indrayudha P, Michavila C, Mukhopadhyay R, Maurer SK, Caulton SG, Emsley J, Dreveny I. 2018. The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel. Journal of Biological Chemistry 293:17362-17374

Weinstock J, Wu J, Cao P, Kingsbury WD, McDermott JL, Kodrasov MP, McKelvey DM, Suresh Kumar KG, Goldenberg SJ, Mattern MR, Nicholson B+1 more. 2012. Selective dual inhibitors of the cancer-related deubiquitylating proteases USP7 and USP47. ACS Medicinal Chemistry Letters 3:789-792

Whitlock NC, Trostel SY, Wilkinson S, Terrigino NT, Hennigan ST, Lake R, Carrabba NV, Atway R, Walton ED, Gryder BE, Capaldo BJ, Ye H, Sowalsky AG+3 more. 2020. MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity. Oncogene 39:5663-5674

Wosnitzer MS, Mielnik A, Dabaja A, Robinson B, Schlegel PN, Paduch DA. 2014. Ubiquitin specific protease 26 (USP26) expression analysis in human testicular and extragonadal tissues indicates diverse action of USP26 in cell differentiation and tumorigenesis. PLOS ONE 9:e98638

Xiong B, Huang J, Liu Y, Zou M, Zhao Z, Gong J, Wu X, Qiu C. 2021. Ubiquitin-specific protease 2a promotes hepatocellular carcinoma progression via deubiquitination and stabilization of RAB1A. Cellular Oncology 44:329-343

Xiong Y, Yuan L, Chen S, Xu H, Peng T, Ju L, Wang G, Xiao Y, Wang X. 2020. WFDC2 suppresses prostate cancer metastasis by modulating EGFR signaling inactivation. Cell Death & Disease 11:537

Xu F, Ma Y, Huang W, Gao J, Guo M, Li J, Kong L, Liang G, Du R, Xu Q, Wu X+1 more. 2020. Typically inhibiting USP14 promotes autophagy in M1-like macrophages and alleviates CLP-induced sepsis. Cell Death & Disease 11:666

Xu J, Chen D, Jin L, Chen Z, Tu Y, Huang X, Xue F, Xu J, Chen M, Wang X, Chen Y+1 more. 2021. Ubiquitously specific protease 4 inhibitor-Vialinin A attenuates inflammation and fibrosis in S100-induced hepatitis mice through Rheb/mTOR signalling. Journal of Cellular and Molecular Medicine 25:1140-1150

Ye Y, Scheel H, Hofmann K, Komander D. 2009. Dissection of USP catalytic domains reveals five common insertion points. Molecular BioSystems 5:1797-1808

Zhang F, Zhao Y, Sun Y. 2021. USP2 is an SKP2 deubiquitylase that stabilizes both SKP2 and its substrates. Journal of Biological Chemistry 297:101109

Zhang J, Wang J, Luan T, Zuo Y, Chen J, Zhang H, Ye Z, Wang H, Hai B. 2019. Deubiquitinase USP9X regulates the invasion of prostate cancer cells by regulating the ERK pathway and mitochondrial dynamics. Oncology Reports 41:3292-3304

Zhong M, Zhou L, Fang Z, Yao YY, Zou JP, Xiong JP, Xiang XJ, Deng J. 2021. Ubiquitin-specific protease 15 contributes to gastric cancer progression by regulating the Wnt/β-catenin signaling pathway. World Journal of Gastroenterology 27:4221-4235

Zhu H, Yan F, Yuan T, Qian M, Zhou T, Dai X, Cao J, Ying M, Dong X, He Q, Yang B+1 more. 2020. USP10 promotes proliferation of hepatocellular carcinoma by deubiquitinating and stabilizing YAP/TAZ. Cancer Research 80:2204-2216