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Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4.
Coleman, Daniel J; Sampson, David A; Sehrawat, Archana; Kumaraswamy, Anbarasu; Sun, Duanchen; Wang, Yuzhuo; Schwartzman, Jacob; Urrutia, Joshua; Lee, Ahn R; Coleman, Ilsa M; Nelson, Peter S; Dong, Xuesen; Morrissey, Colm; Corey, Eva; Xia, Zheng; Yates, Joel A; Alumkal, Joshi J.
Afiliación
  • Coleman DJ; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • Sampson DA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • Sehrawat A; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • Kumaraswamy A; Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • Sun D; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Computational Biology Program, Oregon Health & Science University, Portland, OR, USA.
  • Wang Y; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
  • Schwartzman J; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • Urrutia J; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • Lee AR; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
  • Coleman IM; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Nelson PS; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Dong X; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
  • Morrissey C; Department of Urology, University of Washington, Seattle, WA, USA.
  • Corey E; Department of Urology, University of Washington, Seattle, WA, USA.
  • Xia Z; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Computational Biology Program, Oregon Health & Science University, Portland, OR, USA.
  • Yates JA; Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • Alumkal JJ; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. Electronic address: jalumkal@med.umic
Neoplasia ; 22(6): 253-262, 2020 06.
Article en En | MEDLINE | ID: mdl-32403054
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Tumores Neuroendocrinos / Histona Demetilasas / Proteínas del Tejido Nervioso Tipo de estudio: Prognostic_studies Límite: Humans / Male Idioma: En Revista: Neoplasia Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Tumores Neuroendocrinos / Histona Demetilasas / Proteínas del Tejido Nervioso Tipo de estudio: Prognostic_studies Límite: Humans / Male Idioma: En Revista: Neoplasia Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos