TY - JOUR
T1 - Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer
AU - Nguyen, Thanh
AU - Sridaran, Dhivya
AU - Chouhan, Surbhi
AU - Weimholt, Cody
AU - Wilson, Audrey
AU - Luo, Jingqin
AU - Li, Tiandao
AU - Koomen, John
AU - Fang, Bin
AU - Putluri, Nagireddy
AU - Sreekumar, Arun
AU - Feng, Felix Y.
AU - Mahajan, Kiran
AU - Mahajan, Nupam P.
N1 - Funding Information:
N.P.M. is a recipient of NIH/NCI grants (1R01CA208258, 5R01CA227025, and 1R01CA273054), Prostate Cancer Foundation (PCF) grant (17CHAL06) and Department of Defense award (PC200201). S.Y.R. Dent provided GCN5 and PCAF MEFs. The technical assistance of Petra Erdmann-Gilmore, Yiling Mi and Rose Connors is gratefully acknowledged. The Proteomics experiments were performed at the Washington University Proteomics Shared Resource (WU-PSR), which is supported by the WU Institute of Clinical and Translational Sciences (NCATS UL1 TR000448), the Mass Spectrometry Research Resource (NIGMS P41 GM103422) and the Siteman Comprehensive Cancer Center Support Grant (NCI P30 CA091842). This work has been supported in part by the Proteomics and Metabolomics Core Facility at the Moffitt Cancer Center, an NCI designated Comprehensive Cancer Center (P30-CA076292). The technical assistance of Vasanta Putluri and Danthasinghe Waduge Badrajee Piyarathna for global lipidomics profiling is gratefully acknowledged. This project was supported by CPRIT Proteomics and Metabolomics Core Facility to N.P. (RP210227), NIH (P30 CA125123), and Dan L. Duncan Cancer Center.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85163127848&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-38887-7
DO - 10.1038/s41467-023-38887-7
M3 - Article
C2 - 37296155
AN - SCOPUS:85163127848
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3357
ER -