Histone lactylation boosts SET8, driving pancreatic cancer progression and angiogenesis via MTA1/NuRD complex.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers globally, characterized by aggressive progression and poor survival rates, largely due to late diagnosis and limited effective treatments. The precise mechanisms driving PDAC pathogenesis are still being uncovered, particularly regarding epigenetic regulation. While lysine methyltransferase SET domain-containing protein 8 (SET8) has been implicated in various cancers, its specific role in PDAC and its interaction with metabolic reprogramming, such as histone lactylation, have been poorly understood. This study addresses this critical gap, exploring how SET8 and a novel post-translational modification contribute to tumor progression.

Researchers evaluated SET8 expression and prognostic relevance in PDAC using immunohistochemical staining and bioinformatics analysis of clinical databases. To identify protein interactions, affinity purification coupled with mass spectrometry (MS), co-immunoprecipitation (Co-IP), and glutathione S-transferase (GST) pull-down assays were performed. The functional impact of the SET8/MTA1/NuRD complex was assessed via 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 to evaluate tumorigenesis, angiogenesis, and metastasis.

SET8 expression was significantly upregulated in PDAC tissues and correlated with poor prognosis in patients. Mechanistically, SET8 physically interacted with the MTA1/NuRD complex through direct binding to MTA1, confirmed by Co-IP and GST pull-down assays. This SET8/MTA1/NuRD complex epigenetically repressed tumor suppressor genes, notably SOCS2, through chromatin remodeling. Depletion of either SET8 or MTA1 consistently reduced tumorigenesis, angiogenesis, and metastasis in experimental models. Conversely, overexpression of SET8 promoted oncogenic phenotypes in an MTA1-dependent manner. The study further revealed that lactate dehydrogenase A (LDHA)-mediated histone lactylation directly drove SET8 expression, establishing a novel link between metabolic reprogramming and epigenetic dysregulation in PDAC progression.

SET8 expression was significantly upregulated in PDAC and correlated with poor prognosis, with its oncogenic functions driven by LDHA-mediated histone lactylation.