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.
Nature communications. 2023 Jun 09*** epublish ***
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, Nupam P Mahajan
Department of Surgery, Cancer Research Building, Washington University in St Louis, 660 Euclid Ave., St Louis, MO, 63110, USA., Siteman Cancer Center, Cancer Research Building, Washington University in St Louis, 660 Euclid Ave., St Louis, MO, 63110, USA., Division of Public Health Sciences, Cancer Research Building, Washington University in St Louis, 660 Euclid Ave., St Louis, MO, 63110, USA., Bioinformatics Research Core, Center of Regenerative Medicine, Department of Developmental Biology, Washington University at St. Louis, St Louis, MO, 63110, USA., Molecular Oncology and Molecular Medicine, Moffitt Cancer Center, Tampa, FL, 33612, USA., Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA., Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, 94158, USA., Department of Surgery, Cancer Research Building, Washington University in St Louis, 660 Euclid Ave., St Louis, MO, 63110, USA. .