Takayama Ken-Ichi, Suzuki Takashi, Tsutsumi Shuichi, Fujimura Tetsuya, Takahashi Satoru, Homma Yukio, Urano Tomohiko, Aburatani Hiroyuki, Inoue Satoshi
Departments of Anti-Aging Medicine (K.T., T.U., S.I.) and Geriatric Medicine (K.T., T.U., S.I.) and Department of Urology (T.F., Y.H.), Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Pathology (T.S.), Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan; Genome Science Division (Sh.T., H.A.), Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan; Department of Urology (Sa.T.), Nihon University School of Medicine, Itabashi-ku, Tokyo 173-0032, Japan; and Division of Gene Regulation and Signal Transduction (S.I.), Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, 350-1241, Japan.
Mol Endocrinol. 2014 Dec;28(12):2012-24. doi: 10.1210/me.2014-1171.
The transcriptional network of the androgen receptor (AR), a key molecule of prostate cancer, is frequently modulated by interactions with other transcriptional factors such as forkhead box protein A1 (FOXA1). However, global regulatory mechanisms of AR signaling mediated by such factors have not been well investigated. Here we conducted a chromatin immunoprecipitation sequence analysis, which revealed that another FOX family, FOXP1, is specifically regulated by both AR and FOXA1. We also found that FOXP1 acts as a tumor suppressor in prostate cancer through inhibiting cell proliferation and migration. We generated an extensive global map of FOXP1 binding sites and found that FOXP1 is directly involved in AR-mediated transcription. We demonstrated that FOXP1 has a repressive effect on AR-induced transcriptional activity or histone modification in enhancer regions. Moreover, by a global analysis of androgen-mediated transcriptional networks, we observed enrichment of FOXP1 binding genes in the gene cluster negatively regulated by FOXP1. Evaluation of FOXP1 expression in clinical samples indicated that the decreased expression of FOXP1 is another prognostic factor of prostate cancer. Taken together, our results suggest a novel mechanism in which AR-induced FOXP1 functions as a direct modulator of the AR and FOXA1 centric global transcriptional network.
雄激素受体（AR）是前列腺癌的关键分子，其转录网络常通过与其他转录因子（如叉头框蛋白A1（FOXA1））相互作用而受到调控。然而，由这些因子介导的AR信号通路的整体调控机制尚未得到充分研究。在此，我们进行了染色质免疫沉淀测序分析，结果显示另一个FOX家族成员FOXP1受AR和FOXA1共同特异性调控。我们还发现FOXP1在前列腺癌中通过抑制细胞增殖和迁移发挥肿瘤抑制作用。我们绘制了一份广泛的FOXP1结合位点全局图谱，发现FOXP1直接参与AR介导的转录过程。我们证明FOXP1对增强子区域中AR诱导的转录活性或组蛋白修饰具有抑制作用。此外，通过对雄激素介导的转录网络进行全局分析，我们观察到FOXP1结合基因在受FOXP1负调控的基因簇中富集。对临床样本中FOXP1表达的评估表明，FOXP1表达降低是前列腺癌的另一个预后因素。综上所述，我们的研究结果提示了一种新机制，即AR诱导的FOXP1作为以AR和FOXA1为中心的全局转录网络的直接调节因子发挥作用。
