Polycomb group proteins are often dysregulated in cancer, leading to disruption of epigenetic landscapes and acquisition of cancer hallmarks. Chromobox 8 (CBX8) is a core component of canonical polycomb repressive complex 1, however, its role in transcriptional regulation and in ovarian carcinoma progression has not been extensively investigated. In this study, we find that CBX8 is up-regulated in ovarian cancer. Overexpression and knockdown approaches show that CBX8 facilitates the growth and migration of CAOV3, A2780, and SKOV3 cells in vitro. Consistently, depletion of CBX8 suppresses the growth and metastasis of ovarian carcinoma in vivo. Mechanistically, RNA-seq assays together with functional rescue experiments identify a tumor suppressor, SUSD2, as the functional target of CBX8 in ovarian carcinoma cells. Significantly, FLAG affinity coupled with mass spectrometry discovers that CBX8 interacts with a subunit of inhibitor of acetyltransferases (INHAT), SET, which also promotes the growth and migration of A2780 cells. CBX8 and SET co-bind to the promoter of SUSD2 to establish H2AK119ub1 and prevent the acetylation of histone H3, resulting in transcriptional suppression of SUSD2. Implications: Our study uncovers a novel mechanism CBX8 explores to execute gene repression, and provides new therapeutic targets for ovarian carcinoma.
Background: Genes participating in chromatin organization and regulation are frequently mutated or dysregulated in cancers. ATP-dependent chromatin remodelers (ATPCRs) play a key role in organizing genomic DNA within chromatin, therefore regulating gene expression. The oncogenic role of ATPCRs and the mechanism involved remains unclear. Methods: We analyzed the genomic and transcriptional aberrations of the genes encoding ATPCRs in The Cancer Genome Atlas (TCGA) cohort. A series of cellular experiments and mouse tumor-bearing experiments were conducted to reveal the regulatory function of CHD7 on the growth of colorectal cancer cells. RNAseq and ATAC-seq approaches together with ChIP assays were performed to elucidate the downstream targets and the molecular mechanisms.Results: Our data showed that many ATPCRs represented a high frequency of somatic copy number alterations, widespread somatic mutations, remarkable expression abnormalities, and significant correlation with overall survival, suggesting several somatic driver candidates including chromodomain helicase DNA-binding protein 7 (CHD7) in colorectal cancer. We experimentally demonstrated that CHD7 promotes the growth of colorectal cancer cells in vitro and # These authors contributed equally to this work.
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