Abstract 2532: MicroRNA-1205 directly binds to FRYL and suppresses aggressive prostate cancer

Abstract

Abstract High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (mCRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). Resistance to second generation ADTs leads to the progression to AR-independent neuroendocrine PCa (NEPC), which is observed in nearly 1 in 5 men with mCRPC and is associated with very poor outcome. PCa neuroendocrine differentiation (PCND) is observed in treatment related NEPC, however, this mechanism is poorly understood. Therefore, further understanding of PCND in ADT resistance may prevent poorer outcomes. The 8q24 chromosomal locus is an important prostate cancer (PCa) susceptibility region containing genetic variants associated with increased PCa incidence and aggressiveness. PVT1 is a gene located within this region that encodes microRNA-1205 (miR-1205), whose function is largely unknown. We have previously reported that miR-1205 is underexpressed in a cohort of histologically confirmed PCa tissue obtained from moAA, when compared to normal tissue and is also underexpressed in vitro in CRPC cells, when compared to non-CRPC cells. We also demonstrated that exogenous miR-1205 significantly inhibited tumor volume in CRPC-derived xenograft male NOD/SCID gamma mice, suggesting that miR-1205 is a tumor suppressor. To understand the molecular mechanism of miR-1205, we demonstrated that miR-1205 directly targets Fry-like (FRYL) by performing an RNA pulldown assay. FRYL is predicted to regulate dendritic branching leading to the hypothesis that FRYL plays a role in PCND. To examine miR-1205 regulation of FRYL in PCND in vitro, LNCaP cells were cultured under androgen deprivation conditions for fourteen days. We observed FRYL mRNA overexpresssion and a significant reduction of miR-1205 expression in LNCaP-PCND cells when compared to undifferentiated LNCaP cells. To further determine whether this mechanism drives PCND, miR-1205 was inhibited in RWPE-1 and LNCaP androgen-sensitive cells. As a result, FRYL protein expression was increased along with neuroendocrine marker expression (Neuron specific enolase 2) when compared to cells transfected with a negative control. To determine whether PCND is driven directly through FRYL activity, FRYL was silenced using an siRNA in PC-3 cells (model of NEPC). Interestingly, knockdown of FRYL did not reveal a decrease of neuroendocrine markers, suggesting that miR-1205 may induce PCND independently of FRYL. Further investigation into the role of miR-1205 and FRYL in PCND is required. Further understanding this molecular mechanism may provide novel insights into overcoming ADT resistance in aggressive PCa. Citation Format: Michelle K. Naidoo, Fayola Levine, Xavier Graña, Olorunseun Ogunwobi. MicroRNA-1205 directly binds to FRYL and suppresses aggressive prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2532.