Abstract
Background
N6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined.
Methods
The expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments.
Results
Dysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo–YAP signaling, reprogramming the expression of Hippo target genes.
Conclusions
Our results revealed a new mechanism by which the Hippo–YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression.
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Details
1 Shandong University, Department of Hematology, Shandong Provincial Hospital, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)
2 Shandong Provincial Hospital Affiliated to Shandong First Medical University, Department of Hematology, Jinan, China (GRID:grid.410638.8) (ISNI:0000 0000 8910 6733)
3 Shandong University, Department of Hematology, Shandong Provincial Hospital, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174); Shandong Provincial Hospital Affiliated to Shandong First Medical University, Department of Hematology, Jinan, China (GRID:grid.410638.8) (ISNI:0000 0000 8910 6733); Shandong Provincial Engineering Research Center of Lymphoma, Jinan, China (GRID:grid.410638.8); Branch of National Clinical Research Center for Hematologic Diseases, Jinan, China (GRID:grid.410638.8); The First Affiliated Hospital of Soochow University, National Clinical Research Center for Hematologic Diseases, Suzhou, China (GRID:grid.429222.d) (ISNI:0000 0004 1798 0228)