HDAC3 Deficiency Promotes Liver Cancer through a Defect in H3K9ac/H3K9me3 Transition
HDAC3 Deficiency Promotes Liver Cancer through a Defect in H3K9ac/H3K9me3 Transition
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HDAC3 缺陷通过 H3K9ac/H3K9me3 转换缺陷促进肝癌。
DOI：
10.1158/0008-5472.can-18-3767
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发表时间：
2019-07-15
期刊：
影响因子：
11.2
通讯作者：
Bu, Hong
中科院分区：
文献类型：
--
作者：
Ji, Hongjie;Zhou, Yongjie;Bu, Hong
DNA 损伤会引发多种癌症，特别是肝细胞癌 (HCC)，但 DNA 损伤与肿瘤发生之间的内在联系仍不清楚。由于其作为表观遗传和转录调节因子的作用，组蛋白脱乙酰酶 3 (HDAC3) 对于 DNA 损伤控制至关重要，并且经常在人类 HCC 中异常表达。在这项研究中，我们使用个体 I 类 HDAC 成员缺陷小鼠来证明组蛋白 H3 (H3K9) 中的 K9（DNA 损伤反应复合物组装的关键位点）是 HDAC3 的唯一靶点。 HDAC3 的消除破坏了 H3K9 (H3K9me3) 的脱乙酰化和随后的三甲基化，这是双链断裂 (DSB) 修复的第一步，并导致受损 DNA 的积累。同时，超乙酰化的 H3K9 (H3K9ac) 作为转录激活剂并增强多种信号通路以促进肿瘤发生。这些结果共同表明，HDAC3 以 H3K9ac/H3K9me3 转变为目标，作为控制 DNA 损伤修复和许多肿瘤相关基因转录的关键调节因子。此外，这些发现为肿瘤发生中 DNA 损伤和转录重编程之间的联系提供了新的见解。
DNA damage triggers diverse cancers, particularly hepatocellular carcinoma (HCC), but the intrinsic link between DNA damage and tumorigenesis remains unclear. Due to its role as an epigenetic and transcriptional regulator, histone deacetylase 3 (HDAC3) is essential for DNA damage control and is often aberrantly expressed in human HCC. In this study, we used individual class I HDAC member-deficient mice to demonstrate that K9 in histone H3 (H3K9), which is the critical site for the assembly of DNA damage response complexes, is exclusively targeted by HDAC3. Ablation of HDAC3 disrupted the deacetylation and consequent trimethylation of H3K9 (H3K9me3), the first step in double-strand break (DSB) repair, and led to the accumulation of damaged DNA. Simultaneously, hyperacetylated H3K9 (H3K9ac) served as a transcriptional activator and enhanced multiple signaling pathways to promote tumorigenesis. Together these results show that HDAC3 targets the H3K9ac/H3K9me3 transition to serve as a critical regulator that controls both DNA damage repair and the transcription of many tumor-related genes. Moreover, these findings provide novel insights into the link between DNA damage and transcriptional reprogramming in tumorigenesis.