Tsamouri Maria Malvina, Libertini Stephen J, Siddiqui Salma, Jathal Maitreyee K, Durbin-Johnson Blythe P, Tepper Clifford G, Corey Eva, Luo Jun, Iczkowski Kenneth A, Ghosh Paramita M, Mudryj Maria
Department of Urologic Surgery, Sacramento, CA 95817, USA.
Department of Medical Microbiology and Immunology, Davis, CA 95616, USA; Veterans Affairs-Northern California Health Care System, Mather, CA 95655, USA.
Neoplasia. 2025 Aug;66:101181. doi: 10.1016/j.neo.2025.101181. Epub 2025 May 29.
The androgen receptor (AR) is a pivotal regulator of growth and survival of prostate cancer (PCa) and the majority of lethal castration-resistant prostate cancers (CRPC) remain reliant on AR signaling. PCa exhibits variability in progression and responses to treatment suggesting genetic heterogeneity. Two independent studies identified PCa predisposing single nucleotide polymorphisms (SNPs) within the FAM111A protease gene, but the mechanistic basis of this association remained elusive. Our in vitro and in vivo studies uncovered that AR represses FAM111A in castration sensitive and resistant cells via an AR binding site within the FAM111A gene. FAM111A levels are significantly lower in matched castration-resistant than in castration-sensitive cells and xenografts, and lower in metastatic lesions than in primary tumors. We discovered that FAM111A is AR-repressed in castration sensitive PCa xenograft and multiple PCa cells. Additionally, FAM111A subcellular localization changes dramatically with acquisition of castration resistance, where in castration sensitive cells FAM111A is predominantly in the nucleoli, but with castration resistance it becomes more dispersed in the nucleus and in the cytoplasm. FAM111A depletion in castration sensitive and resistant cells enhances the efficacy of PARP1 inhibitors olaparib and niraparib, consistent with its role in DNA repair. Moreover, FAM111A depletion reduces AR target gene prostate specific antigen (PSA) and transmembrane serine protease 2 (TMPRSS2) transcription, indicating that FAM111A modulates AR-dependent gene expression forming a FAM111A-AR co-regulatory loop in PCa. Our studies argue that AR-dependent FAM111A regulation modulates PCa gene expression, acquisition of castration resistance, and sensitivity to agents that target DNA damage repair.
雄激素受体（AR）是前列腺癌（PCa）生长和存活的关键调节因子，大多数致命的去势抵抗性前列腺癌（CRPC）仍然依赖AR信号传导。PCa在进展和对治疗的反应方面表现出变异性，提示存在基因异质性。两项独立研究在FAM111A蛋白酶基因中鉴定出PCa易感单核苷酸多态性（SNP），但这种关联的机制基础仍不清楚。我们的体外和体内研究发现，AR通过FAM111A基因内的一个AR结合位点在去势敏感和抗性细胞中抑制FAM111A。在匹配的去势抵抗性细胞和异种移植中，FAM111A水平显著低于去势敏感性细胞，在转移灶中低于原发性肿瘤。我们发现FAM111A在去势敏感的PCa异种移植和多种PCa细胞中被AR抑制。此外，随着去势抵抗性的获得，FAM111A亚细胞定位发生显著变化，在去势敏感细胞中FAM111A主要位于核仁，但随着去势抵抗性的出现，它在细胞核和细胞质中变得更加分散。在去势敏感和抗性细胞中敲低FAM111A可增强PARP1抑制剂奥拉帕利和尼拉帕利的疗效，这与其在DNA修复中的作用一致。此外，敲低FAM111A可降低AR靶基因前列腺特异性抗原（PSA）和跨膜丝氨酸蛋白酶2（TMPRSS2）的转录，表明FAM111A调节AR依赖性基因表达，在PCa中形成FAM111A-AR共调节环。我们的研究表明，AR依赖性FAM111A调节可调节PCa基因表达、去势抵抗性的获得以及对靶向DNA损伤修复药物的敏感性。
