TRAF6调控HDAC3的去乙酰化作用促进c-Myc基因表达和蛋白稳定性的机制及其在肝癌发生中的作用

c-Myc是肝癌恶性转化的关键调控分子。除了基因扩增或重排，c-Myc的表达调控仍不清楚。前期我们发现TRAF6与c-Myc的表达在临床肝癌组织标本中存在显著的正相关性，且两者的高表达与病人预后不良紧密相关。机制研究初步揭示TRAF6极有可能通过与HDAC3的相互作用催化其发生K63连接的泛素化，并进一步调控核心组蛋白H3K9以及c-Myc蛋白的乙酰化水平，最终促进c-Myc基因的表达以及抑制CHIP所介导的c-Myc蛋白的泛素化及降解。基于此，我们提出TRAF6通过与HDAC3的相互作用调控c-Myc的基因表达及其蛋白稳定性构成一种新型的调控机制，并参与到肝癌的发生发展。本研究拟应用基因修饰小鼠模型、肝癌相关细胞系以及临床肝癌组织标本从整体动物水平、细胞水平及临床标本等多方面阐明TRAF6调控c-Myc表达的机制，并探讨它们在肝癌发生中的重要作用，以期明确其临床意义。

c-Myc plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). However, except for gene amplifications or rearrangement of c-Myc, precisely how c-Myc is regulated in hepatocarcinogenesis remains poorly understood. Using human liver cancer tissues, we found that TRAF6 positively correlates with c-Myc at both the mRNA and protein levels, and high TRAF6 and c-Myc expression is associated with an unfavorable prognosis. Mechanistically, we observed that TRAF6 interacts with and ubiquitinates HDAC3 with K63-linked ubiquitin chains, which leads to acetylation of histone H3 at K9 and c-Myc protein, thereby epigenetically enhancing the mRNA expression of c-Myc，and enhancing the c-Myc protein stability by regulating CHIP-mediated c-Myc ubiquitination and degradation. Based on these findings, we here hypothesize that TRAF6 dually regulates c-Myc expression via interaction with HDAC3 in liver tumorigenesis. We will use mice, liver cancer cell lines and clinical liver cancer tissues to uncover the potential role and clinical signification of TRAF6/HDAC3/c-Myc axis in liver tumorigenesis.