Language

English

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

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.

Keywords

Male, Humans, Androgens, Prostatic Neoplasms, Castration-Resistant, Histones, Acetylation, Cell Line, Tumor, Receptors, Androgen, Lipids, Prostate, Gene silencing, Prostate cancer

Published Open-Access

yes

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