Abstract 3395: Alternative splicing of the MEAF6 gene promotes neuroendocrine prostate cancer development

Abstract

Abstract In response to the selection pressures exerted by potent androgen receptor (AR) pathway inhibitors (ARPI), adenocarcinoma prostate cancer (PCa) cells can undergo an adaptive process of cellular phenotype reprogramming termed neuroendocrine trans-differentiation. With this AR-bypass mechanism of survival emerges a lethal treatment-resistant PCa subtype called treatment-induced neuroendocrine PCa (t-NEPC). t-NEPC is becoming a major clinical issue as it is estimated to affect >25% of advanced-stage PCa patients with the level of incidences predicted to rise as a result of the extensive applications of ARPI in the clinic. This underscores the gravity of our aims to delineate the molecular underpinnings of t-NEPC to inform future therapies that prevent or mitigate t-NEPC development. In this study, we have identified a splice variant of the MYST/Esa1-associated factor 6 (MEAF6) gene, MEAF6-1, that is highly expressed in t-NEPC tumor biopsies as well as neuroendocrine cell lines of prostate and lung cancers. We show that the neuronal RNA splicing factor, SRRM4, stimulates MEAF6-1 splicing. Enhanced MEAF6-1 expression in prostate adenocarcinoma cell lines does not induce neuroendocrine trans-differentiation of these cells. Rather, it stimulates cell proliferation, anchorage-independent cell growth, invasion, and xenograft tumor growth. Gene microarray identified that these MEAF6-1 actions are in part mediated by the ID1 and ID3 genes. These findings suggest that the MEAF6-1 variant does not induce neuroendocrine differentiation of prostate cancer cells, but facilitates t-NEPC progression through accelerating proliferation of cells that have acquired neuroendocrine phenotypes. Citation Format: Ahn R. Lee, Yinan Li, Ning Xie, Colin C. Collins, Xuesen Dong. Alternative splicing of the MEAF6 gene promotes neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3395. doi:10.1158/1538-7445.AM2017-3395