Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer

Thanh Nguyen, Dhivya Sridaran, Surbhi Chouhan, Cody Weimholt, Audrey Wilson, Jingqin Luo, Tiandao Li, John Koomen, Bin Fang, Nagireddy Putluri, Arun Sreekumar, Felix Y. Feng, Kiran Mahajan and Nupam P. Mahajan ()
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Dhivya Sridaran: Washington University in St Louis
Surbhi Chouhan: Washington University in St Louis
Cody Weimholt: Washington University in St Louis
Audrey Wilson: Washington University in St Louis
Jingqin Luo: Washington University in St Louis
Tiandao Li: Washington University at St. Louis
John Koomen: Moffitt Cancer Center
Bin Fang: Moffitt Cancer Center
Nagireddy Putluri: Baylor College of Medicine
Arun Sreekumar: Baylor College of Medicine
Felix Y. Feng: University of California
Kiran Mahajan: Washington University in St Louis
Nupam P. Mahajan: Washington University in St Louis

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract The 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38887-7

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DOI: 10.1038/s41467-023-38887-7

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