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 - 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 -