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

by De Carvalho, Daniel D. , Chan, Timothy A. , Silverman, Robert H. , Baratchian, Mehdi , Chakraborty, Abhishek A. , Tiwari, Ritika , Li, Jianneng , de Bono, Johann , Varadan, Vinay , Stark, George R. , Khalighi, Sirvan , Berk, Michael , Makarov, Vladimir , Chakravarthy, Ankur , Guerinot, Amy , Sharifi, Nima , Yuan, Wei

in Androgen Antagonists - pharmacology / Androgen Antagonists - therapeutic use / Androgen Receptor Antagonists - pharmacology / Androgen receptors / Androgens / Androgens - pharmacology / Antiandrogens / Biological Sciences / Derepression / DNA Methylation / Double-stranded RNA / Drug resistance / Drug Resistance, Neoplasm / Epigenetics / Gene Silencing / Glucocorticoids / Humans / Interferon / Interferons / Male / Medical Sciences / Methylation / Nitriles - therapeutic use / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - pathology / Receptors / Receptors, Androgen - genetics / Receptors, Androgen - metabolism / Signaling / Tumors

2022

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

2022

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

2022

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Journal Article

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

De Carvalho, Daniel D.,

Chan, Timothy A.,

Silverman, Robert H.,

Baratchian, Mehdi,

Chakraborty, Abhishek A.,

Tiwari, Ritika,

Li, Jianneng,

de Bono, Johann,

Varadan, Vinay,

Stark, George R.,

Khalighi, Sirvan,

Berk, Michael,

Makarov, Vladimir,

Chakravarthy, Ankur,

Guerinot, Amy,

Sharifi, Nima,

Yuan, Wei

2022

Overview

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.

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Publisher

National Academy of Sciences

Subject

Androgen Antagonists - pharmacology

/ Androgen Antagonists - therapeutic use

/ Androgen Receptor Antagonists - pharmacology

/ Androgen receptors

/ Androgens

/ Androgens - pharmacology

/ Antiandrogens