The X-Linked Tumor Suppressor TSPX Interacts and Promotes Degradation of the Hepatitis B Viral Protein HBx via the Proteasome Pathway

Abstract

Hepatitis B virus (HBV) infection is a major risk for hepatocellular carcinoma (HCC), and it is a serious global health problem with two billion people exposed to it worldwide. HBx, an essential factor for viral replication and a putative oncoprotein encoded by the HBV genome, has been shown to promote oncogenic properties at multiple sites in HBV-infected liver cells. The expression level of HBx closely associates with the development and progression of HCC, therefore the mechanism(s) regulating the stability of HBx is important in oncogenesis of HBV-infected cells. We demonstrate that the X-linked tumor suppressor TSPX enhances the degradation of HBx through the ubiquitin-proteasome pathway. TSPX interacts with both HBx and a proteasome 19S lid subunit RPN3 via its C-terminal acidic tail. Most importantly, over-expression of RPN3 protects HBx from, and hence acts as a negative regulator for, proteasome-dependent degradation. TSPX abrogates the RPN3-depedent stabilization of HBx, suggesting that TSPX and RPN3 act competitively in regulation of HBx stability. Since mutation and/or epigenetic repression of X-located tumor suppressor gene(s) could significantly predispose males to human cancers, our data suggest that TSPX-induced HBx degradation could play key role(s) in hepatocarcinogenesis among HBV-infected HCC patients.

Sexual dimorphism in cancer

“…Increased TSPY expression occurs in testicular germ cell tumors 149 , as well as various types of somatic cancer, including melanoma 150 , prostate 151 and liver cancer 152 . Interestingly, while TSPY appears to exert a pro-oncogenic function, it has a homologue on the X chromosome, TSPX, which can be tumour suppressive 153 and protects from hepatitis B viral infection, a major risk for HCC 154 . In fact, both ectopic TSPY activation and TSPX silencing can contribute to the initiation and progression of hepatocellular carcinoma, which, as discussed in a previous section, is a male-predominant cancer 152 (Fig.…”

Sex disparities in melanoma outcomes: The role of biology

“…Interestingly, TSPY is a homologue of TSPX, the tumor suppressor found on the X chromosome, which has an opposing role in the regulation of cell proliferation and tumorigenesis, as discussed above. Such contrasting functions of a pair of sex chromosome homologues likely play important roles in the sexual dimorphisms in certain somatic cancers [141].…”

The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression

“…Such genetic factors include single nucleotide polymorphisms (SNPs) on autosomal genes correlating with the sex difference of HCC [79, 80]. Further, we demonstrated that an X-encoded tumor suppressor TSPX, the homologue of TSPY on the X chromosome, could bind to and promote the proteasomal degradation of the viral oncoprotein HBx [81]. Since men have only one X-chromosome, inactivation and/or mutation of such tumor suppressor gene could increase the risk of HBx-medicated HCC in men [38, 81].…”