Journal Article

Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer

Koomen, John, Mahajan, Kiran, Fang, Bin, Feng, Felix Y., Weimholt, Cody, Putluri, Nagireddy, Nguyen, Thanh, Mahajan, Nupam P., Li, Tiandao, Wilson, Audrey, Luo, Jingqin, Sreekumar, Arun, Sridaran, Dhivya, Chouhan, Surbhi

2023

Overview

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. The molecular mechanisms underlying androgen production in prostate cancer remain to be explored. Here, the authors reveal an epigenetic mark, K130Ac on H2A, following dual-phosphorylation on SREBP1 promoting de novo androgen synthesis to overcome the pharmacological inhibition of androgen synthesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/95 / 38/15 / 45/88 / 49/31 / 631/208/176/2016 / 631/67/589/466 / 692/4025/1752 / 82/58 / Acetylation / Androgen receptors / Androgens / Androgens - metabolism / Biosynthesis / Castration / Cell Line, Tumor / Epigenetics / Histone H2A / Histones / Histones - metabolism / Humanities and Social Sciences / Humans / Kinases / Lipids / Lipogenesis / Lymphocytes / Lymphocytes T / Male / Molecular modelling / multidisciplinary / Nuclear transport / Phosphorylation / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - metabolism / Receptors, Androgen - genetics / Receptors, Androgen - metabolism / Science / Science (multidisciplinary) / Steroidogenesis / Sterol regulatory element-binding protein / Translocation