H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer

Proc Natl Acad Sci U S A. 2022 May 24;119(21):e2114324119. doi: 10.1073/pnas.2114324119. Epub 2022 May 18.

Abstract

Antiandrogen strategies remain the prostate cancer treatment backbone, but drug resistance develops. We show that androgen blockade in prostate cancer leads to derepression of retroelements (REs) followed by a double-stranded RNA (dsRNA)-stimulated interferon response that blocks tumor growth. A forward genetic approach identified H3K9 trimethylation (H3K9me3) as an essential epigenetic adaptation to antiandrogens, which enabled transcriptional silencing of REs that otherwise stimulate interferon signaling and glucocorticoid receptor expression. Elevated expression of terminal H3K9me3 writers was associated with poor patient hormonal therapy outcomes. Forced expression of H3K9me3 writers conferred resistance, whereas inhibiting H3K9-trimethylation writers and readers restored RE expression, blocking antiandrogen resistance. Our work reveals a drug resistance axis that integrates multiple cellular signaling elements and identifies potential pharmacologic vulnerabilities.

Keywords: androgens; enzalutamide; epigenetics; hormonal therapy; 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

  • Androgen Antagonists / pharmacology
  • Androgen Antagonists / therapeutic use
  • Androgen Receptor Antagonists* / pharmacology
  • Androgens / pharmacology
  • DNA Methylation
  • Drug Resistance, Neoplasm
  • Gene Silencing
  • Humans
  • Interferons
  • Male
  • Methylation
  • Nitriles / therapeutic use
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism

Substances

  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Androgens
  • Nitriles
  • Receptors, Androgen
  • Interferons