Department of Urology, China-Japan Friendship Hospital, No. 2 Yinghua Dongjie, Chaoyang District, Beijing, 100029, China.
Department of Urology, China-Japan Friendship Hospital, No. 2 Yinghua Dongjie, Chaoyang District, Beijing, 100029, China.
Biochem Biophys Res Commun. 2020 Mar 26;524(1):16-21. doi: 10.1016/j.bbrc.2019.12.128. Epub 2020 Jan 18.
Activating Transcription Factor 2 (ATF2) is a member of the ATF/CREB bZIP family of transcription factors and an oncogene in prostate cancer. ATF2 has been reported to be a critical substrate of the CUL3-SPOP-RBX1 E3 ubiquitin ligase complex and the recurrent somatic mutation of SPOP has been believed to be a key feature of prostate cancer. However, the deubiquitinating enzyme required for ATF2 stabilization is still unknown. Here, we show that ATF2 is associated with ubiquitin-specific protease 14 (USP14), which increased the protein abundance and transcriptional activity of ATF2. Pharmacologic inhibition or siRNA-mediated depletion of USP14 resulted in the decline and inactivation of ATF2. USP14 deubiquitinates and activates ATF2, resulting in enhanced prostate cancer cells proliferation both in vitro and in vivo. Importantly, silencing of ATF2 largely attuned USP14-mediated prostate cancer cells proliferation. Thus, our data revealed a critical role of USP1-ATF2 axis in the progress of prostate cancer and the inhibition of USP14 might be a promising strategy against prostate cancer.
激活转录因子 2（ATF2）是 ATF/CREB bZIP 家族转录因子的成员，也是前列腺癌中的癌基因。已经报道 ATF2 是 CUL3-SPOP-RBX1 E3 泛素连接酶复合物的关键底物，并且 SPOP 的反复体细胞突变被认为是前列腺癌的一个关键特征。然而，稳定 ATF2 所需的去泛素化酶仍然未知。在这里，我们表明 ATF2 与泛素特异性蛋白酶 14（USP14）相关，USP14 增加了 ATF2 的蛋白丰度和转录活性。USP14 的药理学抑制或 siRNA 介导的耗竭导致 ATF2 的减少和失活。USP14 去泛素化并激活 ATF2，导致体外和体内前列腺癌细胞增殖增强。重要的是，沉默 ATF2 很大程度上调节了 USP14 介导的前列腺癌细胞增殖。因此，我们的数据揭示了 USP1-ATF2 轴在前列腺癌进展中的关键作用，抑制 USP14 可能是对抗前列腺癌的一种有前途的策略。
