Internal medicine

Flutamide

Antiandrogen

Prostate cancer

Antiandrogens

Androgen receptor

Biology

Gene

Cancer

Gene silencing

Gene expression

DNA methylation

Vorinostat

Histone deacetylase

Epigenetic therapy

Histone

Epigenetics

Cancer research

Genetics

Medicine

Proceedings of the National Academy of Sciences

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.

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