Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4.

Abstract

Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program. Despite this distinction, the diagnosis of NEPC is often challenging, demonstrating an urgent need to identify new biomarkers and therapeutic targets. Our prior work demonstrated that the histone demethylase LSD1 (KDM1A) is important for survival of prostate adenocarcinomas, but little was known about LSD1's role in NEPC. Recently, a neural-specific transcript variant of LSD1-LSD1+8a-was discovered and demonstrated to activate neuronal gene expression in neural cells. The splicing factor SRRM4 was previously shown to promote LSD1+8a splicing in neuronal cells, and SRRM4 promotes NEPC differentiation and cell survival. Therefore, we sought to determine if LSD1+8a might play a role in NEPC and whether LSD1+8a splicing was linked to SRRM4. To investigate a potential role for LSD1+8a in NEPC, we examined a panel of prostate adenocarcinoma and NEPC patient-derived xenografts and metastatic biopsies. LSD1+8a was expressed exclusively in NEPC samples and correlated significantly with elevated expression of SRRM4. Using SRRM4-overexpressing cell lines, we determined that SRRM4 mediates alternative splicing of LSD1+8a. Finally, using gain of function studies, we confirmed that LSD1+8a and SRRM4 co-regulate target genes distinct from canonical LSD1. Our findings suggest further study of the interplay between SRRM4 and LSD1+8a and mechanisms by which LSD1+8a regulates gene expression in NEPC is warranted.

• Authors: Daniel J Coleman, David A Sampson, Archana Sehrawat, Anbarasu Kumaraswamy, Duanchen Sun, Yuzhuo Wang, Jacob Schwartzman, Joshua Urrutia, Ahn R Lee, Ilsa M Coleman, Peter S Nelson, Xuesen Dong, Colm Morrissey, Eva Corey, Zheng Xia, Joel A Yates, Joshi J Alumkal
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 22 Issue 6 Pg. 253-262 (06 2020) ISSN: 1476-5586 [Electronic] United States
• PMID: 32403054 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Nerve Tissue Proteins
• SRRM4 protein, human
• Histone Demethylases
• KDM1A protein, human

Topics

• Alternative Splicing (genetics)
• Cell Differentiation (genetics)
• Cell Line, Tumor
• Epigenomics
• Gene Expression Regulation, Neoplastic (genetics)
• Histone Demethylases (genetics)
• Humans
• Male
• Nerve Tissue Proteins (genetics)
• Neuroendocrine Tumors (genetics, pathology)
• Prostatic Neoplasms (genetics)