Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Nat Genet. 2020 Aug;52(8):790-799. doi: 10.1038/s41588-020-0664-8. Epub 2020 Jul 20.

Abstract

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

Publication types

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

MeSH terms

  • Cell Line
  • Cell Line, Tumor
  • Disease Progression
  • Epigenomics / methods
  • Gene Expression Regulation, Neoplastic / genetics
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Humans
  • Male
  • Prostate / pathology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Receptors, Androgen / genetics
  • Regulatory Sequences, Nucleic Acid / genetics

Substances

  • Hepatocyte Nuclear Factor 3-alpha
  • Receptors, Androgen