Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer

Author:

Nguyen Thanh,Sridaran DhivyaORCID,Chouhan Surbhi,Weimholt Cody,Wilson Audrey,Luo JingqinORCID,Li TiandaoORCID,Koomen JohnORCID,Fang BinORCID,Putluri Nagireddy,Sreekumar Arun,Feng Felix Y.ORCID,Mahajan Kiran,Mahajan Nupam P.ORCID

Abstract

AbstractThe testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of which sensitizes castration-resistant prostate cancer (CRPC) to androgen synthesis inhibitor, Abiraterone. Further, we identify a distinct CRPC lipid signature resembling lipid profile of prostate cancer in African American (AA) men. Overall, pY-SREBF1/H2A-K130ac signaling explains cancer sex bias and reveal synchronous inhibition of KAT2A and Tyr-kinases as an effective therapeutic strategy.

Funder

U.S. Department of Health & Human Services | NIH | National Cancer Institute

United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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