Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity

Nat Commun. 2020 Nov 3;11(1):5549. doi: 10.1038/s41467-020-19328-1.

Abstract

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10-20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Cell Line, Tumor
  • Cell Lineage*
  • Cell Plasticity*
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Cohort Studies
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Models, Biological
  • Neoplasm Invasiveness
  • Neoplasm Proteins / metabolism
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Protein Subunits / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome / genetics

Substances

  • Chromosomal Proteins, Non-Histone
  • Neoplasm Proteins
  • Nuclear Proteins
  • Protein Subunits
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases