Aberrant activation of epigenetic BRD9-DGAT1 axis promotes lipid droplets deposition and ferroptosis resistance in YAP-high prostate cancer.

Aberrant interplay between epigenetics and metabolism contributes to prostate cancer (PCa) progression and represents a formidable challenge limiting the efficacy of drugs. Elucidation of the epigenetic underpinnings of prostate cancer (PCa) could provide promising insights into the drivers of therapy resistance. Through an unbiased siRNA screen of mSWI/SNF family members, which play a significant role in tumorigenesis, we identified Bromodomain containing 9 (BRD9) as an essential gene for PCa growth. Targeting BRD9 abolished PCa colony formation and migration in vitro, and inhibited orthotopic tumor growth in vivo. YAP/TEAD4 complex bound to the BRD9 promoter to elevate its levels. Integrated CUT&Tag-seq and RNA-seq analyses revealed DGAT1 as an important BRD9 effector. Mechanistically, BRD9 interacted with SREBP1 to co-occupy the DGAT1 promoter, increasing the H3K4me3 enrichment and chromatin accessibility. Additionally, the YAP-BRD9 axis enhanced the lipid droplets (LDs) formation, ferroptosis resistance, and tumorigenesis via inducing DGAT1. The pharmacological inhibition (or depletion) of BRD9 suppressed LDs formation, restored ferroptosis sensitivity, and PCa malignancy. Overall, the BRD9-SREBP1-DGAT1 axis represents a potential epigenetic therapeutic target for YAP-high PCa.