原发性肝癌是我国常见的恶性肿瘤之一，90%以上的肝癌患者是乙型肝炎病毒（HBV）的携带者，研究表明HBV编码的癌基因HBx与众多宿主因子互作密切，干扰宿主细胞的信号转导、基因转录和DNA修复等生理活动，是促进肝癌发生的重要因素，但其具体机制尚不明确。我们证明HBV能同时抑制DNA修复和诱导细胞对顺铂等药物的抗性。为解释这一现象，我们进一步研究了HBx对细胞表观遗传和基因表达调控的干扰：HBx竞争性地解离CRL4-WDR70泛素化酶的组装，通过抑制衰老基因p16（INK4a）位点H2B单泛素化修饰而下调该基因的表达，并阻断细胞衰老机制。本项目将以p16（INK4a）基因表达的表观遗传调控为切入点，探讨HBx通过干扰CRL4-WDR70-H2B泛素化信号通路导致p16（INK4a）启动子局域组蛋白修饰和DNA甲基化调控的紊乱，为阐明HBV相关肝癌的发病/药物耐受机制和筛选药物靶点提供新的思路。

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China and more than 90% of patients with primary liver cancer are carriers of hepatitis B virus (HBV), studies have shown that HBV encoded oncogene HBx can interact with host factors and interfere with the intracellular physiological activities of host cell signal transduction, gene transcription and DNA repair, which is critical for hepatocarcinogenesis, However the mechanism is not clear. We demonstrated that HBV could inhibit DNA repair and induce cell resistance to chemotherapy drugs such as cisplatin. In order to explain this phenomenon, we further studied the effects of HBx on the regulation of cell epigenetic and gene expression: HBx competitively dissociated the assembly of CRL4-WDR70 ubiquitin ligase, which inhibited the expression of p16(INK4a) by down regulating H2B mono-ubiquitination at its gene site and blocked the cell senescence pathway. Taking a start of p16(INK4a) expression, we plan to discuss the disorder of histone modifications and DNA methylation at the gene promoter location cased by deficiency of CRL4-WDR70-uH2B pathway, aimed to provide new ideas for the HBV related hepatocarcinogenesis and screening of drug targets.