Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4.
Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4.
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DOI：
10.1038/onc.2017.137
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发表时间：
2017-09-07
期刊：
影响因子：
8
通讯作者：
Chen LF
中科院分区：
文献类型：
--
作者：
Hu X;Dong SH;Chen J;Zhou XZ;Chen R;Nair S;Lu KP;Chen LF
BRD4通过促进参与癌症发展的基因的转录而成为肿瘤发生中的一个重要因素。然而，BRD4在癌细胞中是如何调控的在很大程度上仍不清楚。在此，我们报道BRD4的稳定性和功能受胃癌细胞中的Pro-异构酶Pin1正向调节。多肽结合和结晶学研究表明，Pin1直接与BRD4的磷酸化苏氨酸(T)204结合，并通过抑制其泛素化来增强BRD4‘S的稳定性。Pin1还催化BRD4的Prolin205异构化，诱导其构象变化，促进其与CDK9的相互作用，提高BRD4‘S的转录活性。在胃癌细胞中用Pin1结合缺陷的BRD4-T204A突变体替换BRD4会降低BRD4‘S的稳定性，通过削弱BRD4与CDK9的相互作用来减弱BRD4介导的基因表达，从而抑制胃癌细胞的增殖、迁移和侵袭以及肿瘤的形成。我们的结果确定BRD4是Pin1的一个新靶点，并表明干扰它们之间的相互作用可能是一种潜在的癌症治疗方法。
BRD4 has emerged as an important factor in tumorigenesis by promoting the transcription of genes involved in cancer development. However, how BRD4 is regulated in cancer cells remains largely unknown. Here, we report that the stability and functions of BRD4 are positively regulated by prolyl-isomerase PIN1 in gastric cancer cells. PIN1 directly binds to phosphorylated threonine (T) 204 of BRD4 as revealed by peptide binding and crystallographic studies and enhances BRD4’s stability by inhibiting its ubiquitination. PIN1 also catalyses the isomerization of proline 205 of BRD4 and induces its conformational change, which promotes its interaction with CDK9 and increases BRD4’s transcriptional activity. Substitution of BRD4 with PIN1 binding-defective BRD4-T204A mutant in gastric cancer cells reduces BRD4’s stability, attenuates BRD4-mediated gene expression by impairing its interaction with CDK9, and suppresses gastric cancer cell proliferation, migration and invasion, and tumor formation. Our results identify BRD4 as a new target of PIN1 and suggest that interfering with their interaction could be a potential therapeutic approach for cancer treatment.
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