Histone lactylation boosted SET8 potentiates carcinogenesis and angiogenesis of pancreatic ductal adenocarcinoma by cooperating with MTA1/NuRD complex.

BACKGROUND

The pathophysiological role of lysine methyltransferase SET domain-containing protein 8 (SET8) in pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. Emerging evidence suggests that histone lactylation, a novel post-translational modification, may influence tumor progression. However, the interplay between SET8 and lactate metabolism in PDAC pathogenesis has not been elucidated.

METHODS

Immunohistochemical staining and bioinformatics analysis of clinical databases were performed to evaluate SET8 expression and its prognostic relevance in PDAC. Affinity purification coupled with mass spectrometry (MS), co-immunoprecipitation (Co-IP), and glutathione S-transferase (GST) pull-down assays were conducted to identify interactions between SET8 and the MTA1/NuRD complex. Functional roles of the SET8/MTA1/NuRD complex were assessed using chromatin immunoprecipitation (ChIP)-seq, RT-qPCR, western blot, wound healing, transwell invasion, endothelial tube formation, in vivo Chicken Yolk Sac Membrane (YSM) assays, and Masson staining.

RESULTS

SET8 expression was significantly upregulated in PDAC and correlated with poor prognosis. SET8 physically interacted with the MTA1/NuRD complex via direct binding to MTA1, as confirmed by Co-IP and GST pull-down assays. The SET8/MTA1/NuRD complex repressed tumor suppressor genes, including SOCS2, through chromatin remodeling. Depletion of SET8 or MTA1 reduced tumorigenesis, angiogenesis, and metastasis. Overexpression of SET8 promoted oncogenic phenotypes in an MTA1-dependent manner. Mechanistically, lactate dehydrogenase A (LDHA)-mediated histone lactylation drove SET8 expression, linking metabolic reprogramming to epigenetic dysregulation.

CONCLUSIONS

This study identifies SET8 as a proto-oncogene in PDAC, whose expression is regulated by histone lactylation. The SET8/MTA1/NuRD complex facilitates tumor progression by epigenetically silencing SOCS2, highlighting a crosstalk between histone methylation and deacetylation. Targeting the lactylation-SET8/MTA1/NuRD axis may offer a novel therapeutic strategy for PDAC, particularly by restoring SOCS2-mediated tumor suppression. These findings deepen our understanding of metabolic-epigenetic interplay in cancer and provide actionable insights for clinical intervention.