The Role And Molecular Mechanism Of EZH2 In The Treatment Of Hepatocellular Carcinoma And The Development Of Glycoprotein Gp130 In HBV - Related

Part1:Sorafenib suppresses growth and survival of hepatoma cells by accelerating degradation of enhancer of zeste homolog2Enhancer of zeste homolog2(EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes that regulate cancer cell growth and survival. It is overexpressed in hepatocellular carcinoma (HCC) with a clinical significance that remains obscure. Sorafenib, a multikinase inhibitor, has been used as a first-line therapeutic drug and shown clinical efficiency for advanced-stage HCC patients. In the present study, we found that sorafenib lowered the protein level of EZH2through accelerating proteasome-mediated EZH2degradation in hepatoma cells. Overexpression of EZH2reversed sorafenib-induced cell growth arrest, cell cycle arrest, and cell apoptosis dependent on histone methyltransferase activity in hepatoma cells. More importantly, shRNA-mediated EZH2knockdown or EZH2inhibition with3-deazaneplanocin A treatment promoted sorafenib-induced hepatoma cell growth arrest and apoptosis. Sorafenib altered the hepatoma epigenome by reducing EZH2and H3K27trimethylation. These results revealed a novel therapeutic mechanism underlying sorafenib treatment in suppressing hepatoma growth and survival by accelerating EZH2degradation. Genetic deletion or pharmacological ablation of EZH2made hepatoma cells more sensitive to sorafenib, which helps provide a strong framework for exploring innovative combined therapies for advanced-stage HCC patients. Part2:Hepatitis B virus (HBV) infection promotes hepatocellular carcinoma development by attenuating gp130degradationMost hepatocellular carcinoma (HCC) develops in cirrhotic livers after prolonged inflammation, indicating that inflammation play an important role in the onset and progression of HCC. Although the importance of inflammatory cytokines and cytokine receptors in inflammation associated with tumor has been highlighted, the dysregulations of cytokine receptors in cancer cells remain poorly understood. We reported that hepatitis B virus (HBV) infection in hepatoma cells resulted in increased endogenous protein level of pro-inflammatory cytokine family receptor gp130via hepatitis B virus X protein (HBx),and HBx could attenuate gp130degradation, but not directly increased the expression of IL6ST genes. By stable HBx expression, increased the stability of gp130protein resulted in enhanced cell proliferation, induced G1-S cell cycle progression, and blunted cellular apoptosis in vitro. Furthermore, the effect of promoted tumor growth via stable HBx expression by increasing the stability of gp130was shown in a nude mouse xenograft transplantation model. Besides, we also found high expression of gp130positively correlated with the present of microsatellite nodules and HBsAg, liver cirrhotic status, high stage of tumor, and matastasis in tumor from patients with HCC. Our results revealed a novel function of HBx in tumor development through attenuating gp130degradation, which could be a putative molecular mechanism mediating HBV-associated hepatocarcinogenesis and progression. Role of poly comb group protein EZH2-mediated oncogenic activity in tumor progression and recurrenceEpigenetic regulators represent a promising new class of therapeutic targets for cancer. Enhancer of zeste homolog2(EZH2), the catalytic subunit of Polycomb repressive complex2(PRC2), silences gene expression via its histone methyltransferase activity, and plays a key role in controlling biological processes. EZH2is highly expressed in wide range of cancer types, and overexpression of EZH2is often correlated with advanced stages of human cancer progression, poor prognosis and recurrence. Besides, EZH2oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Therefore, blocking EZH2expression or activity or targeting the non-PRC2function of EZH2in metastatic, hormone-refractory prostate cancer may represent a promising strategy for anticancer and recurrence treatment. In this review, we review the current understanding of the mechanisms underlying EZH2regulation alongside the function of EZH2gene targets that are involved in tumor progression and recurrence and recent findings of cancer therapies that target EZH2or its downstream cascades. Finally, we consider prospects for intergrating EZH2blockade into strategy for developing epigenentic or combination therapies.