Takayama Ken-ichi, Suzuki Takashi, Tsutsumi Shuichi, Fujimura Tetsuya, Urano Tomohiko, Takahashi Satoru, Homma Yukio, Aburatani Hiroyuki, Inoue Satoshi
Department of Anti-Aging Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Department of Geriatric Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Oncotarget. 2015 Feb 10;6(4):2263-76. doi: 10.18632/oncotarget.2949.
Androgen receptor (AR) signaling is essential for the development of prostate cancer. Here, we report that runt-related transcription factor (RUNX1) could be a key molecule for the androgen-dependence of prostate cancer. We found RUNX1 is a target of AR and regulated positively by androgen. Our RUNX1 ChIP-seq analysis indicated that RUNX1 is recruited to AR binding sites by interacting with AR. In androgen-dependent cancer, loss of RUNX1 impairs AR-dependent transcription and cell growth. The RUNX1 promoter is bound by enhancer of zeste homolog 2 (EZH2) and is negatively regulated by histone H3 lysine 27 (K27) trimethylation. Repression of RUNX1 is important for the growth promotion ability of EZH2 in AR-independent cells. In clinical prostate cancer samples, the RUNX1 expression level is negatively associated with EZH2 and that RUNX1 loss correlated with poor prognosis. These results indicated the significance of RUNX1 for androgen-dependency and that loss of RUNX1 could be a key step for the progression of prostate cancer.
雄激素受体（AR）信号传导对于前列腺癌的发展至关重要。在此，我们报告称， runt相关转录因子（RUNX1）可能是前列腺癌雄激素依赖性的关键分子。我们发现RUNX1是AR的一个靶点，并受雄激素正向调控。我们的RUNX1染色质免疫沉淀测序（ChIP-seq）分析表明，RUNX1通过与AR相互作用被招募到AR结合位点。在雄激素依赖性癌症中，RUNX1的缺失会损害AR依赖性转录和细胞生长。RUNX1启动子与zeste同源物2（EZH2）结合，并受组蛋白H3赖氨酸27（K27）三甲基化的负调控。RUNX1的抑制对于EZH2在雄激素非依赖性细胞中的生长促进能力很重要。在临床前列腺癌样本中，RUNX1表达水平与EZH2呈负相关，且RUNX1缺失与预后不良相关。这些结果表明RUNX1对雄激素依赖性的重要性，且RUNX1的缺失可能是前列腺癌进展的关键步骤。
