BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis.
BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis.
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BRD 4通过E2 F/miR-106 b/p21轴调节胃癌细胞的细胞衰老。
DOI：
10.1038/s41419-017-0181-6
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发表时间：
2018-02-12
影响因子：
9
通讯作者：
Chen LF
中科院分区：
文献类型：
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作者：
Dong X;Hu X;Chen J;Hu D;Chen LF
针对BET蛋白溴结构域的小分子具有很强的抗肿瘤活性，已成为潜在的癌症治疗药物。然而，这些抑制物抗增殖活性的潜在机制仍未完全确定。在本研究中，我们证实了BET抑制剂JQ1通过诱导细胞衰老来抑制胃癌细胞的增殖和侵袭。在胃癌组织中过度表达的BRD4的缺失，而不是其他BET蛋白的缺失，重现了JQ1诱导的细胞衰老，细胞SA-β-Gal活性增加，p21水平升高。此外，我们还发现依赖于BRD4的miR-106b-5p的表达在转录后水平调节p21的水平，miR-106b-5p针对p21mRNA的3‘-UTR区。MiR-106b-5p过表达可阻止JQ1诱导的p21表达和BRD4抑制相关的细胞衰老，而miR-106b-5p抑制剂上调p21并诱导细胞衰老。最后，我们证明抑制E2F抑制BRD4与miR-106b-5p启动子的结合并抑制其转录，导致胃癌细胞中p21水平升高和细胞衰老。我们的结果揭示了BRD4通过E2F/miR-106b-5p/p21轴调节细胞衰老来调控癌细胞增殖的新机制，并为BET抑制剂作为潜在的抗癌药物提供了新的见解。
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.
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影响因子：
8
作者：
Hu X;Dong SH;Chen J;Zhou XZ;Chen R;Nair S;Lu KP;Chen LF
通讯作者：
Chen LF
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
19
作者：
Blow, JJ;Hodgson, B
通讯作者：
Hodgson, B
影响因子：
13.6
作者：
Ghari F;Quirke AM;Munro S;Kawalkowska J;Picaud S;McGouran J;Subramanian V;Muth A;Williams R;Kessler B;Thompson PR;Fillipakopoulos P;Knapp S;Venables PJ;La Thangue NB
通讯作者：
La Thangue NB
DOI：
10.4049/jimmunol.1502261
发表时间：
2016-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chen J;Wang Z;Hu X;Chen R;Romero-Gallo J;Peek RM Jr;Chen LF
通讯作者：
Chen LF