ERG-Mediated Coregulator Complex Formation Maintains Androgen Receptor Signaling in Prostate Cancer

Cancer Res. 2020 Nov 1;80(21):4612-4619. doi: 10.1158/0008-5472.CAN-20-2044. Epub 2020 Sep 15.

Abstract

The TMPRSS2-ERG fusion is the most common genomic rearrangement in human prostate cancer. However, in established adenocarcinoma, it is unknown how the ERG oncogene promotes a cancerous phenotype and maintains downstream androgen receptor (AR) signaling pathways. In this study, we utilized a murine prostate organoid system to explore the effects of ERG on tumorigenesis and determined the mechanism underlying prostate cancer dependence on ERG. Prostate organoids lacking PTEN and overexpressing ERG (Pten-/- R26-ERG) faithfully recapitulated distinct stages of prostate cancer disease progression. In this model, deletion of ERG significantly dampened AR-dependent gene expression. While ERG was able to reprogram the AR cistrome in the process of prostate carcinogenesis, ERG knockout in established prostate cancer organoids did not drastically alter AR binding, H3K27ac enhancer, or open chromatin profiles at these reprogrammed sites. Proteomic analysis of DNA-bound AR complexes demonstrated that ERG deletion causes a loss of recruitment of critical AR coregulators and basal transcriptional machinery, including NCOA3 and RNA polymerase II, but does not alter AR binding itself. Together, these data reveal a novel mechanism of ERG oncogene addiction in prostate cancer, whereby ERG facilitates AR signaling by maintaining coregulator complexes at AR bound sites across the genome. SIGNIFICANCE: These findings exploit murine organoid models to uncover the mechanism of ERG-mediated tumorigenesis and subsequent oncogenic dependencies in prostate cancer.

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

  • Animals
  • Gene Expression Regulation, Neoplastic / physiology*
  • Male
  • Mediator Complex / metabolism
  • Mice
  • Oncogene Proteins / metabolism*
  • Organoids
  • Prostatic Neoplasms / metabolism*
  • Receptors, Androgen / metabolism*
  • Signal Transduction / physiology*
  • Transcriptional Regulator ERG / metabolism*

Substances

  • ERG protein, mouse
  • Mediator Complex
  • Oncogene Proteins
  • Receptors, Androgen
  • Transcriptional Regulator ERG