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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)253-262
Number of pages10
JournalNeoplasia (United States)
Volume22
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • Epigenetics
  • LSD1
  • LSD1+8a
  • Neuroendocrine prostate cancer
  • SRRM4

ASJC Scopus subject areas

  • Cancer Research

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  • Cite this

    Coleman, D. J., Sampson, D. A., Sehrawat, A., Kumaraswamy, A., Sun, D., Wang, Y., Schwartzman, J., Urrutia, J., Lee, A. R., Coleman, I. M., Nelson, P. S., Dong, X., Morrissey, C., Corey, E., Xia, Z., Yates, J. A., & Alumkal, J. J. (2020). Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4. Neoplasia (United States), 22(6), 253-262. https://doi.org/10.1016/j.neo.2020.04.002