Home Blog of Signal Transduction DNA Damage/DNA Repair HDAC RBBP8/CtIP suppresses P21 expression by interacting with CtBP and BRCA1 in gastric cancer

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RBBP8/CtIP suppresses P21 expression by interacting with CtBP and BRCA1 in gastric cancer

RB Binding Protein 8 (RBBP8) was previously reported being involved in DNA double-strand break (DSB) repair in cancers. However, there is no systematic study about the specific functions and related mechanisms of RBBP8 in gastric carcinogenesis. Through immunohistochemistry staining of paired gastric cancer (GC) tissues, adjacent high-grade intraepithelial neoplasia (HGIEN) tissues, and non-cancerous tissues, we found RBBP8 expression was upregulated in both HGIEN and GC tissues. Functional experiments showed the knockdown of RBBP8 inhibited cell proliferation and colony formation ability. This is mainly achieved through the role of RBBP8 in facilitating G1/S transition and promoting Cyclin D1 and CDK4 level. Then the interaction between RBBP8, BRCA1, and CtBP was revealed by co-immunoprecipitation (co-IP) and immunofluorescence confocal imaging. Moreover, we found RBBP8 acted as an adapter in this complex and RBBP8 overexpression enhanced the nucleus location of BRCA1. RBBP8 overexpression could inhibit P21 expression and HDAC (histone deacetylase) inhibitor Trichostatin A (TSA) eliminated this effect. The HDAC activity of CtBP-RBBP8-BRCA1 complex was also further verified by HDAC activity assay. Through Chromatin immunoprecipitation (ChIP), we found RBBP8 could induce P21 promoter histone deacetylation and inhibit P21 transcription. In conclusion, we found RBBP8 could promote the G1/S transition of GC cells by inhibiting P21 level. Moreover, we revealed the chromatin modification role of RBBP8, which could suppress the histone acetylation level of P21 promoter by recruiting CtBP co-repressor complex to BRCA1 binding site.

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S1045 TSA (Trichostatin A) TSA (Trichostatin A) is an HDAC inhibitor with IC50 of ~1.8 nM in cell-free assays.

Related Targets

HDAC