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

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. [Display omitted] •CHD4 facilitates DNA hypermethylation•CHD4 knockdown reactivates hypermethylated genes•Inhibiting CHD4 blunts tumorigenesis•High level of CHD4 in tumor indicates poor prognosis Xia et al. show that CHD4 is recruited by OGG1 and ZMYND8, respectively, to interact with oxidative DNA damage sites and double-strand breaks. CHD4 recruits repressive chromatin proteins to these sites and helps maintain DNA hypermethylation-associated transcriptional silencing of tumor suppressor genes.