ZNF143-Mediated H3K9 Trimethylation Upregulates CDC6 by Activating MDIG in Hepatocellular Carcinoma
ZNF143-Mediated H3K9 Trimethylation Upregulates CDC6 by Activating MDIG in Hepatocellular Carcinoma
复制标题
ZNF143 介导的 H3K9 三甲基化通过激活肝细胞癌中的 MDIG 上调 CDC6
DOI：
10.1158/0008-5472.can-19-3226
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发表时间：
2020-06-15
期刊：
影响因子：
11.2
通讯作者：
Li, Jinjun
中科院分区：
文献类型：
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作者：
Zhang, Lili;Huo, Qi;Li, Jinjun
这些发现描述了ZNF 143促进HCC增殖的机制，并为探索人类肝癌临床治疗的新靶点和策略提供了重要线索。锌指蛋白143（ZNF 143）属于锌指蛋白家族，通过结合序列特异性DNA而具有转录因子活性。ZNF 143在肝细胞癌（HCC）中的确切生物学作用尚未研究。在这里，我们报告ZNF 143在肝癌组织中过表达，其过表达与预后不良相关。功能获得和丧失实验表明，ZNF 143在体外和体内促进HCC细胞增殖、集落形成和肿瘤生长。ZNF 143通过激活细胞分裂周期6（CDC 6）加速肝癌细胞周期进程。ZNF 143通过直接激活组蛋白去甲基化酶矿物尘诱导基因（MDIG）的转录，进而减少H3 K9 me 3在CDC 6启动子区域的富集，从而促进CDC 6的表达。HCC中ZNF 143的表达与MDIG和CDC 6的表达相关。总的来说，我们提出了ZNF 143-MDIG-CDC 6癌蛋白轴的模型，该模型为ZNF 143提供了新的见解，ZNF 143可能作为HCC的治疗靶点。重要性：这些发现描述了ZNF 143促进HCC增殖的机制，并为探索人类肝癌临床治疗的新靶点和策略提供了重要线索。
These findings describe the mechanism by which ZNF143 promotes HCC proliferation and provide important clues for exploring new targets and strategies for clinical treatment of human liver cancer. Zinc finger protein 143 (ZNF143) belongs to the zinc finger protein family and possesses transcription factor activity by binding sequence-specific DNA. The exact biological role of ZNF143 in hepatocellular carcinoma (HCC) has not been investigated. Here we report that ZNF143 is overexpressed in HCC tissues and its overexpression correlates with poor prognosis. Gain- and loss-of-function experiments showed that ZNF143 promoted HCC cell proliferation, colony formation, and tumor growth in vitro and in vivo. ZNF143 accelerated HCC cell-cycle progression by activating cell division cycle 6 (CDC6). Mechanistically, ZNF143 promoted expression of CDC6 by directly activating transcription of histone demethylase mineral dust–induced gene (MDIG), which in turn reduced H3K9me3 enrichment in the CDC6 promoter region. Consistently, ZNF143 expression correlated significantly with MDIG and CDC6 expression in HCC. Collectively, we propose a model for a ZNF143–MDIG–CDC6 oncoprotein axis that provides novel insight into ZNF143, which may serve as a therapeutic target in HCC. Significance: These findings describe the mechanism by which ZNF143 promotes HCC proliferation and provide important clues for exploring new targets and strategies for clinical treatment of human liver cancer.