BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis

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.

miR‐106b‐5p promotes aggressive progression of hepatocellular carcinoma via targeting RUNX3

“…Growing evidence show that miRNAs may be potential therapeutic targets for their roles in regulating either oncogenes or tumor suppressor genes. Recent studies have revealed that miR‐106b‐5p may play an oncogenic role in various cancer types by promoting malignant cell viability and invasion . For example, Lu et al revealed that miR‐106b‐5p could mediate the constitutive activation of Wnt/β‐catenin signaling, and promote renal cell carcinoma aggressiveness and stem cell‐like phenotypes; Wei et al indicated that miR‐106b‐5p overexpression promoted proliferation and inhibited apoptosis by downregulating BTG3 expression in vitro, as well as xenograft tumor formation in vivo; Liu et al found that miR‐106b‐5p could boost glioma tumorigensis by targeting multiple tumor suppressor genes, including RBL1, RBL2, and CASP8; Yu et al demonstrated that miR‐106b‐5p enhanced the sensitivity of nonsmall‐cell lung cancer cell line A549/DDP to cisplatin by targeting the expression of PKD2.…”

“…It belongs to the miR‐106b seed family which has been indicated to be closely associated with cell proliferation, cell cycle, and cell motility . Accumulating studies have reported that miR‐106b‐5p plays an important role in various cancers through diverse mechanisms . Particularly, Shi et al found that the expression of miR‐106b‐5p was higher in HCC tissues and cell lines than that in nontumor tissues and hepatocytes, respectively.…”

“…13 Accumulating studies have reported that miR-106b-5p plays an important role in various cancers through diverse mechanisms. [14][15][16][17][18][19][20] Particularly, Shi et al 21 found that the expression of miR-106b-5p was higher in HCC tissues and cell lines than that in nontumor tissues and hepatocytes, respectively. The authors also indicated that miR-106b-5p upregulation promoted stem cell-like properties of HCC cells by targeting PTEN via PI3K/Akt pathway.…”

Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1

“…24 Recent reports proposed that JQ1, a selective inhibitor of BET proteins, exerts antigrowth effects in many types of cancer, inducing cell cycle arrest in cancer cells followed by the downregulation of the MYC oncogene. [25][26][27][28][29][30] However, the efficacy of JQ1 for BTC remains unknown. 30 In the present study, we investigated the therapeutic efficacy of JQ1 for ICC cells and identified the possible involvement of mutant IDH1 in the sensitivity to JQ1.…”

“…Bromodomain and extraterminal domain (BET) family proteins (BRD2, BRD3, BRD4, and BRDT) recognize acetylated lysine residues on histone tails and facilitate transcriptional activation through the recruitment of transcriptional regulatory complexes . Recent reports proposed that JQ1, a selective inhibitor of BET proteins, exerts antigrowth effects in many types of cancer, inducing cell cycle arrest in cancer cells followed by the downregulation of the MYC oncogene . However, the efficacy of JQ1 for BTC remains unknown .…”