前列腺癌
生物
癌症研究
雄激素受体
染色质免疫沉淀
转录因子
内科学
癌症
发起人
遗传学
基因表达
医学
基因
作者
Daisuke Obinata,Ken‐ichi Takayama,Kyoko Fujiwara,Takashi Suzuki,Seiichiro Tsutsumi,Noboru Fukuda,Hiroki Nagase,Tetsuya Fujimura,Tomohiko Urano,Yukio Homma,Hiroyuki Aburatani,Satoru Takahashi,Satoshi Inoue
出处
期刊:Oncogene
[Springer Nature]
日期:2016-06-06
卷期号:35 (49): 6350-6358
被引量:38
摘要
Androgen receptor (AR) functions as a ligand-dependent transcription factor to regulate its downstream signaling for prostate cancer progression. AR complex formation by multiple transcription factors is important for enhancer activity and transcriptional regulation. However, the significance of such collaborative transcription factors has not been fully understood. In this study, we show that Oct1, an AR collaborative factor, coordinates genome-wide AR signaling for prostate cancer growth. Using global analysis by chromatin immunoprecipitation sequencing (ChIP-seq), we found that Oct1 is recruited to AR-binding enhancer/promoter regions and facilitates androgen signaling. Moreover, a major target of AR/Oct1 complex, acyl-CoA synthetase 3 (ACSL3), contributes to tumor growth in nude mice, and its high expression is associated with poor prognosis in prostate cancer patients. Next, we examined the therapeutic effects of pyrrole-imidazole polyamides that target the Oct1-binding sequence identified in the center of the ACSL3 AR-binding site. We observed that treatment with Oct1 polyamide severely blocked the Oct1 binding at the ACSL3 enhancer responsible for its transcriptional activity and ACSL3 induction. In addition, Oct1 polyamides suppressed castration-resistant tumor growth and specifically repressed global Oct1 chromatin association and androgen signaling in prostate cancer cells, with few nonspecific effects on basal promoter activity. Thus, targeting Oct1 binding could be a novel therapeutic strategy for AR-activated castration-resistant prostate cancer.
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