Quan Yongjun, Cui Yun, Wahafu Wasilijiang, Liu Yuexin, Ping Hao, Zhang Xiaodong
Department of Urology, Beijing Chaoyang Hospital, Capital Medical University Beijing 100020, China.
Department of Urology, Beijing Tongren Hospital, Capital Medical University Beijing 100730, China.
Am J Cancer Res. 2020 May 1;10(5):1608-1629. eCollection 2020.
Prostate cancer (PCa) is one of the most prevalent malignancies in men. However, the molecular mechanism controlling the transformation of androgen-dependent PCa (ADPC) to castration-resistant PCa (CRPC) is largely unknown. Androgen receptor (AR) signaling has been reported to play a key role in this process; thus, searching for the novel AR co-activator is important for identifying the mechanism underlying PCa progression. In this study, we focused on the function of mixed lineage leukemia-5α (MLL5α), an epigenetic regulator that exhibits aberrant expression in PCa. MLL5α was the primary expressed form of MLL5 protein in PCa cells and it significantly suppressed proliferation, invasion, and migration in PCa cell lines. Upon stimulation with dihydrotestosterone (DHT), knockdown of MLL5α significantly suppressed N-myc downstream regulated gene 1 (NDRG1) and Kallikrein-related peptidase 3 (KLK3) expression. MLL5α directly bound with AR on the androgen response elements (AREs) and recruited H3K4me3 to the promoters of NDRG1 and KLK3. Downregulation of NDRG1 partially restored the cell invasion and migration suppressed by MLL5α. As evaluated by the proliferation of PCa cells, overexpression of MLL5α synergistically promoted sensitivity to enzalutamide (ENZ) treatment. In PCa patients, MLL5α expression was lower in the high Gleason score (GS) (GS > 7) group than in the low GS (GS < 7) group. In conclusion, suppression of AR/NDRG1 signaling via androgen deprivation therapy (ADT) may be a potential mechanism of CRPC progression. MLL5α significantly suppressed PCa progression by promoting AR/NDRG1 signaling, indicating that regulating MLL5α expression may be a potential treatment approach for patients with advanced PCa.
前列腺癌（PCa）是男性中最常见的恶性肿瘤之一。然而，控制雄激素依赖性前列腺癌（ADPC）向去势抵抗性前列腺癌（CRPC）转变的分子机制在很大程度上尚不清楚。据报道，雄激素受体（AR）信号在这一过程中起关键作用；因此，寻找新型AR共激活因子对于确定PCa进展的潜在机制很重要。在本研究中，我们聚焦于混合谱系白血病-5α（MLL5α）的功能，它是一种在PCa中表达异常的表观遗传调节因子。MLL5α是PCa细胞中MLL5蛋白的主要表达形式，它显著抑制PCa细胞系的增殖、侵袭和迁移。在用二氢睾酮（DHT）刺激后，敲低MLL5α显著抑制N- myc下游调控基因1（NDRG1）和激肽释放酶相关肽酶3（KLK3）的表达。MLL5α在雄激素反应元件（AREs）上直接与AR结合，并将H3K4me3募集到NDRG1和KLK3的启动子上。NDRG1的下调部分恢复了MLL5α抑制的细胞侵袭和迁移。通过PCa细胞增殖评估，MLL5α的过表达协同促进了对恩杂鲁胺（ENZ）治疗的敏感性。在PCa患者中，高Gleason评分（GS）（GS>7）组的MLL5α表达低于低GS（GS<7）组。总之，通过雄激素剥夺疗法（ADT）抑制AR/NDRG1信号可能是CRPC进展的潜在机制。MLL5α通过促进AR/NDRG1信号显著抑制PCa进展，表明调节MLL5α表达可能是晚期PCa患者的一种潜在治疗方法。
