Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Oncogene. 2017 Nov 9;36(45):6213-6224. doi: 10.1038/onc.2017.226. Epub 2017 Jul 10.
Current therapeutic regimens for prostate cancer focus on targeting androgen receptor (AR) signaling. However, the AR is a key factor in luminal epithelium differentiation and was shown to have a role as a tumor suppressor. Thus, its inhibition may activate oncogenic pathways that contribute to metastatic castration-resistant prostate cancer (CRPC). Herein, we report a novel tumor promoter, ZBTB46, which is negatively regulated by AR signaling via microRNA (miR)-1-mediated downregulation. ZBTB46 is associated with malignant prostate cancer and is essential for metastasis. Its overexpression can overcome the antitumor effects of miR-1 and promote androgen-independent proliferation. We demonstrated that ZBTB46 can transcriptionally regulate SNAI1, a key epithelial-to-mesenchymal transition (EMT) driver, which could contribute to induction of the EMT after androgen-deprivation therapy and metastasis. Our findings are supportive of the model that disruption of AR's function may predispose prostate cancer to progress to metastatic CRPC.
目前治疗前列腺癌的方法主要集中在靶向雄激素受体 (AR) 信号上。然而，AR 是管腔上皮分化的关键因素，并且被证明具有肿瘤抑制因子的作用。因此，其抑制可能会激活导致转移性去势抵抗性前列腺癌 (CRPC) 的致癌途径。在此，我们报告了一种新型肿瘤促进剂 ZBTB46，它通过 microRNA (miR)-1 介导的下调受到 AR 信号的负调控。ZBTB46 与恶性前列腺癌相关，是转移所必需的。其过表达可以克服 miR-1 的抗肿瘤作用并促进雄激素非依赖性增殖。我们证明 ZBTB46 可以转录调节 SNAI1，这是 EMT 的关键驱动因素之一，这可能有助于在去势治疗和转移后诱导 EMT。我们的研究结果支持这样一种模型，即 AR 功能的破坏可能使前列腺癌更容易进展为转移性 CRPC。
