Alternative RNA splicing of the MEAF6 gene facilitates neuroendocrine prostate cancer progression

// Ahn R. Lee 1 , Yinan Li 1 , Ning Xie 1 , Martin E. Gleave 1 , Michael E. Cox 1 , Colin C. Collins 1 , Xuesen Dong 1 1 Vancouver Prostate Centre, Department of Urologic Sciences, The University of British Columbia, Vancouver V6H 3Z6, Canada Correspondence to: Xuesen Dong, email: xdong@prostatecentre.com Keywords: MEAF6, RNA splicing, tumor progression, neuroendocrine prostate cancer Received: November 25, 2016      Accepted: February 20, 2017      Published: March 02, 2017 ABSTRACT Although potent androgen receptor pathway inhibitors (ARPI) improve overall survival of metastatic prostate cancer patients, treatment-induced neuroendocrine prostate cancer (t-NEPC) as a consequence of the selection pressures of ARPI is becoming a more common clinical issue. Improved understanding of the molecular biology of t-NEPC is essential for the development of new effective management approaches for t-NEPC. In this study, we identify a splice variant of the MYST/Esa1-associated factor 6 (MEAF6) gene, MEAF6-1, that is highly expressed in both t-NEPC tumor biopsies and neuroendocrine cell lines of prostate and lung cancers. We show that MEAF6-1 splicing is stimulated by neuronal RNA splicing factor SRRM4. Rather than inducing neuroendocrine trans-differentiation of cells in prostate adenocarcinoma, MEAF6-1 upregulation stimulates cell proliferation, anchorage-independent cell growth, invasion and xenograft tumor growth. Gene microarray identifies 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 rather facilitates t-NEPC progression by increasing the proliferation rate of cells that have acquired neuroendocrine phenotypes.