CHD4在启动和维持多个肿瘤抑制基因的表观遗传抑制中具有致癌功能。
CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes.
作者信息
Xia Limin, Huang Wenjie, Bellani Marina, Seidman Michael M, Wu Kaichun, Fan Daiming, Nie Yongzhan, Cai Yi, Zhang Yang W, Yu Li-Rong, Li Huili, Zahnow Cynthia A, Xie Wenbing, Chiu Yen Ray-Whay, Rassool Feyruz V, Baylin Stephen B
机构信息
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
出版信息
Cancer Cell. 2017 May 8;31(5):653-668.e7. doi: 10.1016/j.ccell.2017.04.005.
An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks. CHD4 knockdown activates silenced TSGs, revealing their role for blunting colorectal cancer cell proliferation, invasion, and metastases. High CHD4 and 8-OHdG levels plus low expression of TSGs strongly correlates with early disease recurrence and decreased overall survival.
染色质重塑去乙酰化酶复合物（NuRD）的一个组成部分CHD4在人类结直肠癌中具有致癌作用，它启动并维持肿瘤抑制基因（TSG）的沉默。CHD4招募抑制性染色质蛋白至DNA损伤修复位点，包括DNA甲基转移酶，从而引发DNA的从头甲基化。在TSG处，CHD4的保留有助于维持与DNA高甲基化相关的转录沉默。切除修复蛋白OGG1招募CHD4以应对氧化损伤，使其与损伤诱导的碱基8-羟基脱氧鸟苷（8-OHdG）相互作用，而ZMYND8则将其招募至双链断裂处。敲低CHD4可激活沉默的TSG，揭示其对抑制结肠癌细胞增殖、侵袭和转移的作用。CHD4和8-OHdG的高表达以及TSG的低表达与疾病早期复发和总生存率降低密切相关。
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