Tan Yi-Fan, Zhang Yang, Ge Sheng-Yang, Zhong Fan, Sun Chuan-Yu, Xia Guo-Wei
Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Department of Systems Biology for Medicine, and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cell Death Discov. 2022 Sep 20;8(1):393. doi: 10.1038/s41420-022-01181-4.
The mechanisms by which prostate cancer (PCa) progresses to the aggressive castration-resistant stage remain uncertain. Zinc finger of the cerebellum 5 (ZIC5), a transcription factor belonging to the ZIC family, is involved in the pathology of various cancers. However, the potential effect of ZIC5 on PCa malignant progression has not been fully defined. Here, we show that ZIC5 is upregulated in PCa, particularly in metastatic lesions, in positive association with poor prognosis. Genetic inhibition of ZIC5 in PCa cells obviously attenuated invasion and metastasis and blunted the oncogenic properties of colony formation. Mechanistically, ZIC5 functioned as a transcription factor to promote TWIST1-mediated EMT progression or as a cofactor to strengthen the β-catenin-TCF4 association and stimulate Wnt/β-catenin signaling. Importantly, ZIC5 and the androgen receptor (AR) form a positive feed-forward loop to mutually stimulate each other's expression. AR, in cooperation with its steroid receptor coactivator 3 (SRC-3), increased ZIC5 expression through binding to the miR-27b-3p promoter and repressing miR-27b-3p transcription. In turn, ZIC5 potentiated AR, AR-V7, and AR targets' expression. Besides, ZIC5 inhibition reduced AR and AR-V7 protein expression and enhanced the sensitivity of PCa to enzalutamide (Enz) treatment, both in vitro and in vivo. These findings indicate that the reciprocal activation between AR and ZIC5 promotes metastasis and Enz resistance of PCa and suggest the therapeutic value of cotargeting ZIC5 and AR for the treatment of advanced PCa.
前列腺癌（PCa）进展为侵袭性去势抵抗阶段的机制仍不明确。小脑锌指蛋白5（ZIC5）是一种属于ZIC家族的转录因子，参与多种癌症的病理过程。然而，ZIC5对PCa恶性进展的潜在影响尚未完全明确。在此，我们表明ZIC5在PCa中上调，尤其是在转移灶中，与不良预后呈正相关。在PCa细胞中对ZIC5进行基因抑制明显减弱了侵袭和转移能力，并削弱了集落形成的致癌特性。从机制上讲，ZIC5作为转录因子促进TWIST1介导的上皮-间质转化（EMT）进程，或作为辅因子加强β-连环蛋白-TCF4的结合并刺激Wnt/β-连环蛋白信号通路。重要的是，ZIC5和雄激素受体（AR）形成正反馈环，相互刺激对方的表达。AR与其类固醇受体共激活因子3（SRC-3）协同作用，通过结合miR-27b-3p启动子并抑制miR-27b-3p转录来增加ZIC5的表达。反过来，ZIC5增强AR、AR-V7和AR靶标的表达。此外，ZIC5抑制降低了AR和AR-V7蛋白表达，并增强了PCa在体外和体内对恩杂鲁胺（Enz）治疗的敏感性。这些发现表明AR和ZIC5之间的相互激活促进了PCa的转移和对Enz的耐药性，并提示联合靶向ZIC5和AR治疗晚期PCa的治疗价值。
