HDAC3-BRG1介导DNA损伤快速低精度修复促进肝癌异质化

肿瘤发生多与DNA损伤和某些修复机制失效有关。肝细胞癌（HCC）随体积增大出现进行性异质化（heterogenization），但其遗传学基础还不清楚。肝癌细胞增殖活跃、基因组稳定性差，DNA损伤极为频繁，加之多个修复蛋白常高频突变失活，必须依靠更简捷高效的修复机制才能存活。染色质重塑在DNA损伤修复中至关重要，代表两种染色质重塑调控机制的关键蛋白（酶）HDAC3和BRG1直接参与DNA修复并发挥重要作用，且随着HCC异质化，两者协同升高并提示预后不良。基于对二者在DNA损伤修复及HCC发生发展中的深入研究，我们推测依赖HDAC3-BRG1为核心的修复机制，部分肝癌细胞因被快速修复而存活；又因一些关键蛋白的失活损害了修复精度，存活细胞携带新的遗传缺陷而表现出新的异质性。本研究将验证该假说，进而阐明HDAC3-BRG1修复复合体的关键构成和工作机制，并探讨是否可将其作为抗HCC治疗的新靶点。

The development of cancers is commonly associated with DNA damage caused by various genotoxic stress, particularly with insufficient DNA damage repair mechanism. With the increase of tumor size, hepatocellular carcinoma (HCC) displays continuous heterogenization, however, the underlying genetic changes are still unclear. Because of the extremely active proliferation and poor genomic stability, liver cancer cells suffer very frequent DNA damage daily. In addition, several genes which protein products are involved in DNA damage repair are frequently mutant in HCC, such as TP53 and PI3K family. It is urgent required that the tumor cells develop a novel DNA damage repair mechanism that can rapidly repair the complicated DNA and chromatin damage, and unavoidably, the accuracy of the repair is no longer a priority. The survived tumor cells, carrying new gene defects with inaccurate repair, give rise to a new clone with new heterogeneity. Chromatin remodeling plays an important role in DNA damage repair. Histone deacetylase 3 (HDAC3) and Brahma-related gene-1 (BRG1), the central catalytic subunit of numerous chromatin-modifying enzymatic complexes SWI/SNF, which represent the covalent modification of chromatin and the ATP-dependent chromatin remodeling, respectively, are involved and play critical roles in DNA repair. In addition, both HDAC3 and BRG1 can combine with p53 in DNA damage repair complex, and HDAC3 interacts with BRG1 in a NCoRI suppressor complex. With the development and heterogenization of HCC, both HDAC3 and BRG1 are significantly increased in tumor tissues and often suggest poor prognosis. .Based on our previous work, we propose that HDAC3-BRG1, as the core component of the repair complex, can repair damaged DNA more efficiently and therefore promote the survival of cancer cells. At the same time, due to the lack of repair accuracy, the survived cancer cells carry new mutations and develop new heterogeneity. In this study we set to verify our hypothesis, and then clarify the key components and working mechanism of the HDAC3-BRG1 repair complex. We will then explore whether the inhibition of HDAC3-BRG1 repair complex can be used as a novel target of HCC treatment.