H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer.
Loading...
Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2022-05-24
Date Accepted
2022-03-25
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.
Citation
Proceedings of the National Academy of Sciences of USA, 2022, 119 (21), pp. e2114324119 -
Source Title
Proceedings of the National Academy of Sciences of USA
Publisher
NATL ACAD SCIENCES
ISSN
0027-8424
eISSN
1091-6490
1091-6490
1091-6490
Collections
Research Team
PrCa Targeted Therapy