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BET Inhibition Suppresses Gastric Cancer Cell Proliferation by Inducing Cell Senescence
Author(s) -
Dong Xingchen
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb169
Subject(s) - bromodomain , brd4 , senescence , cell growth , bet inhibitor , microbiology and biotechnology , cell cycle , cancer research , microrna , cell , gene knockdown , cancer cell , cancer , histone , chemistry , biology , cell culture , biochemistry , gene , genetics
The bromodomain and extra‐C terminal domain (BET) proteins are important in mediating cell cycle control, inflammatory cytokine production and developmental programs. BET proteins bind to acetylated histone or non‐histone proteins and serve as transcriptional co‐regulators of gene expression. Small molecules targeting bromodomains of BET proteins, BET inhibitors (BETi), possess strong anti‐tumor activities and have emerged as potential therapeutics in cancer and inflammatory diseases. However, BETi target all the BET family proteins, including Brd2, Brd3, Brd4 and Brdt. The contribution of each BET protein and the detailed mechanism of BETi‐mediated inhibition of cancer cell proliferation remain to be determined. In this study, we demonstrate that BETi JQ1 suppresses the tumorigenicity of gastric cancer cells by targeting Brd4‐mediated microRNA expression. JQ1 inhibits gastric cancer cell proliferation, migration, and invasion by inducing cell senescence. Depletion of Brd4 but not other BET proteins recapitulates JQ1‐induced cell senescence. Furthermore, we demonstrate that knockdown of Brd4 or treatment of cells with JQ1 increase p21 level through down‐regulation of miR‐106b‐5p. Overexpression of miR‐106b‐5p prevents JQ1‐induced p21 expression and cell senescence, whereas miR‐106b‐5p inhibition up‐regulates p21 and induces cell senescence. Finally, we show that JQ1 abolishes the binding of Brd4 to the regulatory element of miR‐106b‐5p to inhibit the expression miR‐106b‐5p. Our results identify a novel function of Brd4 in cancer cell proliferation by modulating cell senescence via miR‐106b‐5p/p21 axis and provide new insights into using BETi as a potential anti‐cancer drug.