Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer

Research output: Contribution to journalArticle

Abstract

Purpose: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood. Experimental Design: We applied mass spectrometry–based proteomics to a unique set of 17 prostate cancer patient–derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. Results: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. Conclusions: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.

Details

Authors
  • Amilcar Flores-Morales
  • Tobias B. Bergmann
  • Charlotte Lavallee
  • Tanveer S. Batth
  • Dong Lin
  • Mads Lerdrup
  • Stine Friis
  • Anette Bartels
  • Gitte Kristensen
  • Hui Xue
  • Ladan Fazli
  • Klaus H. Hansen
  • Martin A. Røder
  • Klaus Brasso
  • Jose M. Moreira
  • Yuzhuo Wang
  • Jesper V. Olsen
  • Colin C. Collins
  • Diego Iglesias-Gato
Organisations
External organisations
  • University of Copenhagen
  • Danish Cancer Society Research Center
  • University of British Columbia
  • Copenhagen University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)595-608
Number of pages14
JournalClinical Cancer Research
Volume25
Issue number2
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes