The dependency of prostate cancer (PCa) growth on androgen receptor (AR) signaling has been harnessed to develop first-line therapies for high-risk localized and metastatic PCa treatment. However, the occurrence of aberrant expression, mutated or splice variants of AR confers resistance to androgen ablation therapy (ADT), radiotherapy or chemotherapy in AR-positive PCa. Therapeutic strategies that effectively inhibit the expression and/or transcriptional activity of full-length AR, mutated AR and AR splice variants have remained elusive. In this study, we report that mithramycin (MTM), an antineoplastic antibiotic, suppresses cell proliferation and exhibits dual inhibitory effects on expression and transcriptional activity of AR and AR splice variants. MTM blocks AR recruitment to its genomic targets by occupying AR enhancers and causes downregulation of AR target genes, which includes key DNA repair factors in DNA damage repair (DDR). We show that MTM significantly impairs DDR and enhances the effectiveness of ionizing radiation or the radiomimetic agent Bleomycin in PCa. Thus, the combination of MTM treatment with RT or radiomimetic agents, such as bleomycin, may present a novel effective therapeutic strategy for patients with high-risk, clinically localized PCa.

前列腺癌 (PCa) 生长对雄激素受体 (AR) 信号的依赖性已被用于开发用于高风险局部和转移性 PCa 治疗的一线疗法。然而，AR 的异常表达、突变或剪接变体的发生赋予 AR 阳性 PCa 对雄激素消融疗法 (ADT)、放疗或化疗的抗性。有效抑制全长 AR、突变 AR 和 AR 剪接变体的表达和/或转录活性的治疗策略仍然难以捉摸。在这项研究中，我们报告了光神霉素 (MTM)，一种抗肿瘤抗生素，抑制细胞增殖，并对 AR 和 AR 剪接变体的表达和转录活性表现出双重抑制作用。MTM 通过占据 AR 增强子阻止 AR 募集到其基因组目标，并导致 AR 目标基因的下调，其中包括 DNA 损伤修复 (DDR) 中的关键 DNA 修复因子。我们表明 MTM 显着损害 DDR 并增强电离辐射或 PCa 中放射模拟剂博来霉素的有效性。因此，MTM 治疗与放疗或放射模拟药物（如博来霉素）的组合可能为高危、临床局部 PCa 患者提供一种新的有效治疗策略。