Epigenetic Control of Androgen Production by Histone H2A Lys130 acetylation

The biosynthesis of androgen from cholesterol in testis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncovered that sterol regulatory element-binding protein 1 (SREBP1) and its switch to hitherto unknown dual-phosphorylated form (pY673/951-SREBP1), acts as an androgen sensor. Androgen deficiency promoted SREBP1 dual-phosphorylation, causing its dissociation from androgen receptor (AR) in its androgen-unbound state, followed by nuclear translocation. SREBP1 recruited KAT2A/GCN5 and deposited novel epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Tumor-derived androgen retained SREBP1 in cytosol, promoting T cell exhaustion, reflected in elevated PD-1 and Tim3. Reversal of H2A-K130ac or pY-SREBP1 sensitized castration-resistant prostate cancer (CRPC) resistant to androgen synthesis inhibitor, Abiraterone. Further, nuclear SREBP1 and H2A-K130ac levels were significantly increased and directly correlated with late stage prostate cancer patients. Global lipidomics analysis revealed a distinct lipid signature in androgen-deprived CRPCs, resembling the lipid profile of prostate cancers of African-American (AA) men. Overall, self-perpetuating pY-SREBP1/H2A-K130ac signaling explains sex bias in cancers and reveal a novel therapeutic vulnerability wherein synchronous inhibition of GCN5 and Tyr-kinases could overcome drug-resistant disease, benefiting AA men with aggressive prostate cancer. Romidepsin (0.5 µM, 18h) treated VCaP cells were cross-linked, chromatin was isolated, and ChIP was performed using H2A-K130ac antibody, followed by sequencing