Hu X, Dong S-H, Chen J, Zhou X Z, Chen R, Nair S, Lu K P, Chen L-F
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA.
Oncogene. 2017 Sep 7;36(36):5177-5188. doi: 10.1038/onc.2017.137. Epub 2017 May 8.
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.
BRD4 通过促进参与癌症发展的基因转录，已成为肿瘤发生中的一个重要因素。然而，BRD4 在癌细胞中是如何被调控的，在很大程度上仍不清楚。在此，我们报告在胃癌细胞中，脯氨酰异构酶 PIN1 正向调控 BRD4 的稳定性和功能。肽结合和晶体学研究表明，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增强 BRD4 的稳定性。PIN1 还催化 BRD4 脯氨酸 205 的异构化并诱导其构象变化，这促进了它与 CDK9 的相互作用并增加了 BRD4 的转录活性。在胃癌细胞中用与 PIN1 结合缺陷的 BRD4-T204A 突变体替代 BRD4，会降低 BRD4 的稳定性，通过损害其与 CDK9 的相互作用减弱 BRD4 介导的基因表达，并抑制胃癌细胞的增殖、迁移和侵袭以及肿瘤形成。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。
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