Publication Date
6-9-2023
Journal
Nature Communications
DOI
10.1038/s41467-023-38887-7
PMID
37296155
PMCID
PMC10256812
PubMedCentral® Posted Date
6-9-2023
PubMedCentral® Full Text Version
Post-Print
Published Open-Access
yes
Keywords
Male, Humans, Androgens, Prostatic Neoplasms, Castration-Resistant, Histones, Acetylation, Cell Line, Tumor, Receptors, Androgen, Lipids, Prostate, Gene silencing, Prostate cancer
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.
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Life Sciences Commons, Medical Cell Biology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Obstetrics and Gynecology Commons, Oncology Commons
Comments
Associated Data