BRD9 recognizes lactate-induced H3K18 lactylation to drive oncogenic chromatin remodeling in hepatocellular carcinoma - PubMed
3 days ago
- #H3K18 lactylation
- #HCC
- #BRD9
- BRD9 identified as a lactyl-lysine reader linking lactate-induced H3K18 lactylation (H3K18la) to chromatin remodeling in hepatocellular carcinoma (HCC).
- Elevated H3K18la levels correlate with poor HCC prognosis.
- BRD9's bromodomain engages H3K18la with weak, transient affinity, distinct from stable H3K18ac binding, enabling it to function as a metabolic-epigenetic sensor.
- H3K18la recruits BRD9 and the ncBAF chromatin remodeling complex to active enhancers and promoters, promoting chromatin accessibility and oncogenic transcription.
- Glycolytic inhibition or BRD9 targeting displaces BRD9 from chromatin, suppresses oncogenes, and impairs HCC proliferation.
- Modulating lactylation via p300 or HDAC inhibition attenuates transcription and reduces tumor viability.
- In vivo, glycolytic inhibition suppresses tumor growth.
- Findings establish a feedforward loop where glycolytic flux promotes H3K18la-dependent BRD9-ncBAF recruitment to sustain oncogenic transcription, defining BRD9 as a critical metabolic-epigenetic mediator and therapeutic target in HCC.