Alteration in expression and subcellular localization of the androgen receptor-regulated FAM111A

The androgen receptor (AR) is a pivotal regulator of growth and proliferation 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. Consistent with AR-dependent FAM111A repression, the two transcripts are reciprocally regulated in metastatic lesions, FAM111A levels are significantly lower in matched castration-resistant than in castration-sensitive LuCaP patient-derived xenograft (PDX) tumors, and lower in metastatic lesions than in primary tumors. We uncovered that 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 PSA and TMPRSS2 transcription, indicating that FAM111A modulates AR-dependent gene expression and forms 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. Overall design: RNA-seq profiling of two cell lines 22Rv1 and LNCaP-AI , AR signaling was reduced by AR-targeting siRNA (siAR) in cells proliferating in steroid depleted media. Non-targeting siRNA (siC) served as a control