Abstract
Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post-transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3′-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b-5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anticancer drugs.
Highlights
Epigenetic regulation of gene expression plays important roles in controlling normal cellular functions as well as abnormal cellular activities in human diseases like cancer
In an effort to understand the contribution of BET to gastric cancer development and the mechanism for BETimediated inhibition of cancer cell proliferation, we found that BRD4 was overexpressed in gastric cancer patient tissues and BET inhibitor JQ1 targeted BRD4 to induce cellular senescence in gastric cancer cells
JQ1 inhibits the proliferation and invasiveness of gastric cancer cells To explore the potential therapeutic effect of BET inhibitors (BETis) on gastric cancer, we first compared the mRNA levels of BETs in gastric cancer patients and normal gastric tissues using data acquired through TCGA Firebrowse portal
Summary
Epigenetic regulation of gene expression plays important roles in controlling normal cellular functions as well as abnormal cellular activities in human diseases like cancer. Three different types of proteins are involved in the epigenetic regulation: enzymes that modify histone or DNA (writers), enzymes that remove modifications on histone or DNA (erasers), and proteins that recognize these modifications (readers)[1]. The bromodomain-containing proteins represent a class of epigenetic readers that recognize acetylated lysines of histone and non-histone proteins via their bromodomains[3]. BRD4, one of the BET (bromodomain and extraterminal) family proteins, has become a key player in transcription, cell cycle control, inflammatory cytokine production and cancer development[4,5]. BRD4 is involved in the development of hematological malignancies and solid tumors, emerging as a promising therapeutic target for cancer treatment[6]. Small molecules targeting bromodomains of BRD4 and other BET family proteins display strong anti-tumor activities, suppressing the proliferation
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