Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Nat Commun. 2018 Nov 27;9(1):5007. doi: 10.1038/s41467-018-07475-5.
TRIM24 is an effector substrate of the E3 ubiquitin ligase adaptor SPOP and becomes stabilized in prostate cancer (PCa) with SPOP mutations. However, how TRIM24 protein is regulated in the vast majority of SPOP-wildtype PCa is unknown. Here we report TRIM28 as a critical upstream regulator of TRIM24. TRIM28 protein interacts with TRIM24 to prevent its ubiquitination and degradation by SPOP. Further, TRIM28 facilitates TRIM24 occupancy on the chromatin and, like TRIM24, augments AR signaling. TRIM28 promotes PCa cell proliferation in vitro and xenograft tumor growth in vivo. Importantly, TRIM28 is upregulated in aggressive PCa and associated with elevated levels of TRIM24 and worse clinical outcome. TRIM24 and AR coactivated gene signature of SPOP-mutant PCa is similarly activated in human PCa with high TRIM28 expression. Taken together, this study provides a novel mechanism to broad TRIM24 protein stabilization and establishes TRIM28 as a promising therapeutic target.
TRIM24 是 E3 泛素连接酶接头 SPOP 的效应底物，在具有 SPOP 突变的前列腺癌 (PCa) 中变得稳定。然而，在绝大多数 SPOP 野生型 PCa 中，TRIM24 蛋白是如何被调控的尚不清楚。在这里，我们报告 TRIM28 是 TRIM24 的关键上游调节因子。TRIM28 蛋白与 TRIM24 相互作用，防止其被 SPOP 泛素化和降解。此外，TRIM28 促进 TRIM24 在染色质上的占据，并且像 TRIM24 一样，增强 AR 信号。TRIM28 促进体外 PCa 细胞增殖和体内异种移植肿瘤生长。重要的是，TRIM28 在侵袭性 PCa 中上调，并与 TRIM24 水平升高和更差的临床结局相关。具有高 TRIM28 表达的人类 PCa 中，同样激活了 SPOP 突变型 PCa 的 TRIM24 和 AR 共激活基因特征。综上所述，本研究提供了一种广泛稳定 TRIM24 蛋白的新机制，并确立了 TRIM28 作为一种有前途的治疗靶点。
