CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

• DOI: 10.1016/j.ccell.2017.04.005
• Publication Date: 2017-05-08T12:32:29Z
• Authors: Limin Xia; Wenjie Huang; Marina Bellani; Michael M. Seidman; Kaichun Wu; Daiming Fan; Yongzhan Nie; Yi Cai; Yang W. Zhang; Li-Rong Yu; Huili Li; Cynthia A. Zahnow; Wenbing Xie; Ray-Whay Chiu Yen; Feyruz V. Rassool; Stephen B. Baylin
• Keywords: 0303 health sciences; Deoxyguanosine; Down-Regulation; DNA Methylation; Epigenetic Repression; HCT116 Cells; Autoantigens; Disease-Free Survival; DNA Glycosylases; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; 8-Hydroxy-2'-Deoxyguanosine; Cell Movement; Animals; Clustered Regularly Interspaced Short Palindromic Repeats; Enhancer of Zeste Homolog 2 Protein; Genes, Tumor Suppressor; DNA (Cytosine-5-)-Methyltransferases; Gene Silencing; Colorectal Neoplasms; Cell Proliferation; DNA Damage

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.