Elevated expression of WSB2 degrades p53 and activates the IGFBP3-AKT-mTOR-dependent pathway to drive hepatocellular carcinoma

Abstract

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.

WSB2: The hidden instigator of hepatocellular carcinoma and lung metastasis

Hepatocellular carcinoma (HCC, a common type of liver cancer) has a low survival rate due to incomplete understanding of its growth. In this research, scientists identified a protein named WSB2 that is overly produced in HCC and linked with poor patient results. The research involved 289 HCC patients and used different methods like gene sequencing, tissue analysis, and cell culture experiments. The scientists discovered that WSB2 interacts with a tumor suppressor protein (protein that prevents cancer growth) named p53, causing its breakdown and promoting cancer growth. This process was found to be independent of another protein, Mdm2, known to degrade p53. The research also showed that a medicine called everolimus, which inhibits a pathway activated by WSB2, could potentially be used to treat HCC. The findings provide new understanding into HCC growth and potential treatments.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.