Abstract B090: Molecular mechanisms of microRNA-1205 in aggressive prostate cancer in men of African ancestry

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 towards second generation ADTs leads to the progression of AR-independent neuroendocrine PCa (NEPC) phenotypes, which are observed in nearly 1 in 5 men with mCRPC and is associated with short survival rates. Moreover, men of African ancestry (moAA) have a higher NEPC incidence and mortality rates, compared to Caucasian males. 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 PCa susceptibility region containing genetic variants associated with increased PCa incidence among moAA. 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). 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 NEPC, we examined RNA sequencing data from a cohort of histologically confirmed NEPC tissues (n=14) and PCa adenocarcinoma tissues (n=30) obtained from TCGA using the cBioPortal platform. We observed increased FRYL mRNA expression in NEPC tissues when compared to PCa adenocarcinoma tissues. In vitro data revealed that FRYL mRNA was overexpressed and miR-1205 was significantly underexpressed after fourteen days of induced PCND differentiation using LNCaP cells when compared to undifferentiated LNCaP cells. Lastly, we performed RNA pulldown, and subsequent RNA sequencing to identify the molecular targets of miR-1205. Interestingly, we observed that in addition to FRYL, the AURKA gene, which is amplified during PCND, was significantly enriched. In conclusion, these data suggest that miR-1205 regulation of FRYL may be a critical mechanism in NEPC. Further understanding this molecular mechanism may provide novel insights into overcoming ADT resistance in aggressive PCa that disproportionally affects moAA. Citation Format: Michelle K Naidoo, Fayola Levine, Xavier Graña-Amat, Olorunseun Ogunwobi. Molecular mechanisms of microRNA-1205 in aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B090.