Oncotarget

Research Papers:

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

Ahn R. Lee, Yinan Li, Ning Xie, Martin E. Gleave, Michael E. Cox, Colin C. Collins and Xuesen Dong _

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Oncotarget. 2017; 8:27966-27975. https://doi.org/10.18632/oncotarget.15854

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Abstract

Ahn R. Lee1, Yinan Li1, Ning Xie1, Martin E. Gleave1, Michael E. Cox1, Colin C. Collins1, Xuesen Dong1

1Vancouver 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.


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