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

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  • Amilcar Flores-Morales
  • Tobias B Bergmann
  • Charlotte Lavallee
  • Tanveer S Batth
  • Dong Lin
  • Mads Lerdrup
  • Stine Friis
  • Anette Bartels
  • Gitte Kristensen
  • Agnieszka Krzyzanowska
  • Hui Xue
  • Ladan Fazli
  • Klaus Hansen
  • M Andreas Røder
  • Klaus Brasso
  • José M Moreira
  • Anders Bjartell
  • Yuzhuo Wang
  • Jesper V Olsen
  • Colin C Collins
  • Diego Iglesias-Gato
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PURPOSE: 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 were correlated to the expression changes in vivoto investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation.

RESULTS: An average of 4881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell cycle regulation and DNA repair were found upregulated 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 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 in 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 p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.

OriginalsprogEngelsk
TidsskriftClinical Cancer Research
Vol/bind25
Udgave nummer2
Sider (fra-til)595-608
ISSN1078-0432
DOI
StatusUdgivet - 2019

ID: 55534447