Abstract
CHD4 maintains epigenetic silencing of tumor suppressor genes to promote tumorigenesis.
Major finding: CHD4 maintains epigenetic silencing of tumor suppressor genes to promote tumorigenesis.
Mechanism: OGG1 and ZMYND8 recruit CHD4 to DNA damage sites, promoting repressive chromatin protein recruitment.
Impact: CHD4 may serve as a potential biomarker or therapeutic target in patients with colorectal cancer.
During DNA damage repair epigenetic events promote transcriptional silencing of nascent transcription to ensure damage repair; however, abnormal DNA methylation and repressive chromatin can sometimes be retained. Xia, Huang, and colleagues found that the chromatin remodeling protein CHD4 is recruited to sites of DNA damage where it promotes silencing of tumor suppressor genes. At sites of DNA single-strand or double-strand breaks CHD4 recruited the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, which are involved in transcriptional repression. Further, CHD4 interacted with EZH2 and G9a, which are responsible for depositing the repressive histone marks H3K27me3 and H3K9me2 respectively, and tightened their binding to chromatin at sites of DNA damage. Inducing double-strand breaks at the promoters of tumor suppressor genes resulted in recruitment of CHD4 and its associated repressive chromatin proteins and silencing of tumor suppressor genes in colorectal cancer cell lines. Depletion of CHD4 reduced DNA methylation, H3K27me3, and H3K9me2, and reactivated expression of eight silenced tumor suppressor genes. CHD4 was recruited to sites of oxidative DNA damage by the base excision repair factor OGG1, whereas it was recruited to double-strand breaks by the zinc-finger protein ZMYND8. CHD4-mediated suppression of tumor suppressor genes promoted migration and invasion in colorectal cancer cell lines and promoted metastasis in vivo. Consistent with these findings, overexpression of CHD4 and high levels of the oxidative damage marker 8-OHdG were associated with enhanced promoter DNA methylation and reduced expression of tumor suppressor genes in human colorectal cancer tissue, which were associated with a poorer prognosis. Moreover, CHD4 expression was higher in metastases than in primary colorectal cancer, and higher in patients who developed colorectal cancer recurrence. The finding that CHD4 has an oncogenic role in maintaining epigenetic silencing of tumor suppressor genes in colorectal cancer suggests that developing CHD4 inhibitors may be beneficial for colorectal cancer treatment. Further, CHD4 and 8-OHdG may be useful as biomarkers in patients with colorectal cancer.
