Abstract
Chromodomain helicase DNA binding protein 5 (CHD5) acts as a tumor suppressor in many cancers. In the present study, we demonstrated that reduced levels of CHD5 in hepatocellular carcinoma (HCC) tissues were significantly associated with metastasis and poor prognosis. Gain-of-function assays revealed that CHD5 suppressed motility and invasion of HCC cells. Subsequent investigations showed that CHD5 was epigenetically silenced by polycomb repressive complex 2 (PRC2)-mediated the trimethylation of histone H3 at lysine 27 (H3K27me3) in HCC cells. Furthermore, overexpression of CHD5 repressed enhancer of zeste homolog 2 (EZH2) and activated PRC2 target genes, such as p16 and p21. Chromatin immunoprecipitation and luciferase reporter assays also showed that CHD5 and EZH2 bind to each other's promoters and inhibit transcription. These findings uncovered, for the first time, a mutual suppression regulation between CHD5 and EZH2, which may provide new insights into their potential therapeutic significance for HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most frequently occurring cancer worldwide [1]
We demonstrated that reduced levels of Chromodomain helicase DNA binding protein 5 (CHD5) in hepatocellular carcinoma (HCC) tissues were significantly associated with metastasis and poor prognosis
We showed that downregulation of CHD5 correlates with HCC metastasis and poor prognosis and that mutual suppression regulation occurs between enhancer of zeste homolog 2 (EZH2) and CHD5 in HCC
Summary
Hepatocellular carcinoma (HCC) is the fifth most frequently occurring cancer worldwide [1]. The chromodomain helicase DNA-binding protein (CHD) family, which takes part in nucleosome remodeling and the regulation of gene expression, is structurally characterized by two N-terminal chromodomains and a helicase-like ATPase motif [13]. Several members of this family have been confirmed to play important roles in tumorigenesis and metastasis. We showed that downregulation of CHD5 correlates with HCC metastasis and poor prognosis and that mutual suppression regulation occurs between EZH2 and CHD5 in HCC
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