An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer

Nat Cell Biol. 2021 Sep;23(9):1023-1034. doi: 10.1038/s41556-021-00743-5. Epub 2021 Sep 6.

Abstract

Cancers adapt to increasingly potent targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumours can escape epithelial lineage confinement and transition to a high-plasticity state as an adaptive response to potent androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumours adopt alternative lineage identities, with changes in chromatin architecture guiding AR transcriptional rerouting. The epigenetic regulator enhancer of zeste homologue 2 (EZH2) co-occupies the reprogrammed AR cistrome to transcriptionally modulate stem cell and neuronal gene networks-granting privileges associated with both fates. This function of EZH2 was associated with T350 phosphorylation and establishment of a non-canonical polycomb subcomplex. Our study provides mechanistic insights into the plasticity of the lineage-infidelity state governed by AR reprogramming that enabled us to redirect cell fate by modulating EZH2 and AR, highlighting the clinical potential of reversing resistance phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Gene Expression Regulation, Neoplastic / genetics*
  • Gene Regulatory Networks / genetics*
  • Gene Regulatory Networks / physiology
  • Humans
  • Male
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Signal Transduction / physiology

Substances

  • AR protein, human
  • Receptors, Androgen
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein