SIRT3 Functions as an Eraser of Histone H3K9 Lactylation to Modulate Transcription for Inhibiting the Progression of Esophageal Cancer

Lysine lactylation (Kla) links lactate metabolism to epigenetic regulation, playing a key role in modulation of gene expression in tumor and immune microenvironment. Our recent study shows that HBO1-mediated histone H3K9la activates the transcription of genes encoding tumorigenesis, suggesting the potential significance of intervening in this Kla site for tumor therapy. Evidence so far indicates that traditional deacetylases can catalyse the removal of Kla, however, the precise demodifying enzyme to histone H3K9la in vivo and functional consequence remain elusive. Herein, we combined an antibody-based proximity labeling approach with mass spectrometry analysis to identify SIRT3 as a major binder to histone H3K9la and showed the specific catalysis of SIRT3 for the removal of lactylation. Molecular docking further revealed the molecular mechanism of the binding of Histone H3K9la to SIRT3. More importantly, SIRT3 can specifically modulate gene transcription by regulating H3K9la, inhibiting the progression of esophageal squamous cancer cells (ESCC). Together, our work identifies the specific delactylase of H3K9la and reveals an H3K9la-mediated molecular mechanism catalysed by SIRT3 for gene transcription regulation in ESCC, and our findings provide an opportunity to investigate the physiological significance of Kla controlled by SIRT3 in cancer.