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

Neoplasia: An International Journal for Oncology Research

Peter S. Nelson¹  Joshua Urrutia²  Yuzhuo Wang³  Anbarasu Kumaraswamy³  Joshi J. Alumkal³  Xuesen Dong³  Zheng Xia³  David A. Sampson³  Ilsa M. Coleman³  Jacob Schwartzman⁴  Ahn R. Lee⁵  Daniel J. Coleman⁵  Archana Sehrawat⁵  Eva Corey⁵  Duanchen Sun⁵  Joel A. Yates⁵  Colm Morrissey⁶ 

[1] Computational Biology Program, Oregon Health &Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA;Science University, Portland, OR, USA;Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA;;Knight Cancer Institute, Oregon Health &Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada;

关键词: Neuroendocrine prostate cancer;    LSD1;    LSD1+8a;    SRRM4;    Epigenetics;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown