Morozov Viacheslav M, Li Ying, Clowers Matthew M, Ishov Alexander M
Department of Anatomy and Cell Biology and Health Cancer Center, University of Florida College of Medicine, Gainesville, FL 32610, USA.
IDP Graduate Program, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Oncotarget. 2017 Jul 8;8(37):62131-62142. doi: 10.18632/oncotarget.19100. eCollection 2017 Sep 22.
Androgen receptor (AR) mediates initiation and progression of prostate cancer (PCa); AR-driven transcription is activated by binding of androgens to the ligand-binding domain (LBD) of AR. Androgen ablation therapy offers only a temporary relief of locally advanced and metastatic PCa, and the disease eventually recurs as a lethal castration-resistant PCa (CRPC) as there is no effective treatment for CRPC patients. Thus, it is critical to identify novel targeted and combinatorial regimens for clinical management of CRPC. Reduction of the repressive epigenetic modification H3K27me2/3 correlates with PCa aggressiveness, while corresponding demethylases JMJD3/UTX are overexpressed in PCa. We found that JMJD3/UTX inhibitor GSK-J4 reduced more efficiently proliferation of AR-ΔLBD cells (CRPC model) compared with isogenic AR-WT cells. Inhibition of JMJD3/UTX protects demethylation of H3K27Me2/3, thus reducing levels of H3k27Me1. We observed that the reduction dynamics of H3K27Me1 was faster and achieved at lower inhibitor concentrations in AR-ΔLBD cells, suggesting that inhibition of JMJD3/UTX diminished proliferation of these cells by hindering AR-driven transcription. In addition, we observed synergy between GSK-J4 and Cabazitaxel, a taxane derivative that is approved for CRPC treatment. Collectively, our results point at the H3K27 demethylation pathway as a new potential therapeutic target in CRPC patients.
雄激素受体（AR）介导前列腺癌（PCa）的起始和进展；雄激素与AR的配体结合域（LBD）结合可激活AR驱动的转录。雄激素剥夺疗法仅能暂时缓解局部晚期和转移性PCa，由于对去势抵抗性PCa（CRPC）患者没有有效的治疗方法，该疾病最终会复发为致命的去势抵抗性前列腺癌。因此，确定用于CRPC临床管理的新型靶向和联合治疗方案至关重要。抑制性表观遗传修饰H3K27me2/3的减少与PCa的侵袭性相关，而相应的去甲基化酶JMJD3/UTX在PCa中过表达。我们发现，与同基因的AR-WT细胞相比，JMJD3/UTX抑制剂GSK-J4能更有效地降低AR-ΔLBD细胞（CRPC模型）的增殖。抑制JMJD3/UTX可保护H3K27Me2/3的去甲基化，从而降低H3k27Me1的水平。我们观察到，在AR-ΔLBD细胞中，H3K27Me1的降低动力学更快，且在较低的抑制剂浓度下即可实现，这表明抑制JMJD3/UTX通过阻碍AR驱动的转录来减少这些细胞的增殖。此外，我们观察到GSK-J4与卡巴他赛（一种被批准用于CRPC治疗的紫杉烷衍生物）之间存在协同作用。总的来说，我们的结果表明H3K27去甲基化途径是CRPC患者新的潜在治疗靶点。
