H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer.
Date
2022-05-24ICR Author
Author
Baratchian, M
Tiwari, R
Khalighi, S
Chakravarthy, A
Yuan, W
Berk, M
Li, J
Guerinot, A
de Bono, J
Makarov, V
Chan, TA
Silverman, RH
Stark, GR
Varadan, V
De Carvalho, DD
Chakraborty, AA
Sharifi, N
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
androgens
enzalutamide
epigenetics
hormonal therapy
prostate cancer
Androgen Antagonists
Androgen Receptor Antagonists
Androgens
DNA Methylation
Drug Resistance, Neoplasm
Gene Silencing
Humans
Interferons
Male
Methylation
Nitriles
Prostatic Neoplasms, Castration-Resistant
Receptors, Androgen
Research team
PrCa Targeted Therapy
Language
eng
Date accepted
2022-03-25
License start date
2022-05-24
Citation
Proceedings of the National Academy of Sciences of USA, 2022, 119 (21), pp. e2114324119 -
Publisher
NATL ACAD SCIENCES
Except where otherwise noted, this item's license is described
as
http://creativecommons.org/licenses/by/4.0/
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