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

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.

Automated summary

Antiandrogen strategies are commonly used in prostate cancer treatment, but they often lead to drug resistance. This study reveals that antiandrogen treatment activates retroelements (REs), which triggers an interferon response and inhibits tumor growth. Furthermore, the study identifies H3K9 trimethylation as an essential epigenetic adaptation to antiandrogens, as it suppresses REs and prevents the activation of interferon signaling and glucocorticoid receptor. The expression of terminal H3K9me3 writers is associated with poor patient outcomes in hormonal therapy.