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

Oncogene volume 39, pages 1273–1289 (2020)Cite this article

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Abstract

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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Acknowledgements

We thank Prof. Guangyong Chen and Ms Rui Xu, Department of Pathology, Beijing Friendship Hospital for the supply of tissue materials and the score assessment for IHC. We thank the Clinical Data and Biobank Resource of Beijing Friendship Hospital for their help in sample collection.

Funding

This work was completely supported by grants from the National Natural Science Foundation of China (81702314); Funding Program for Excellent Talents of Beijing (2017000021469G212); The Digestive Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals (XXZ0201); Beijing Municipal Administration of Hospitals’ Youth Programme (QML20180108).

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Authors and Affiliations

  1. Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050, Beijing, China

    Yang Yu, Lei Chen, Guiping Zhao, Hengcun Li, Qingdong Guo, Shengtao Zhu, Peng Li, Li Min & Shutian Zhang

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  1. Yang Yu
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Correspondence to Li Min or Shutian Zhang.

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Yu, Y., Chen, L., Zhao, G. et al. RBBP8/CtIP suppresses P21 expression by interacting with CtBP and BRCA1 in gastric cancer. Oncogene 39, 1273–1289 (2020). https://doi.org/10.1038/s41388-019-1060-7

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