Journal of translational medicine · 2026
Histone lactylation boosted SET8 potentiates carcinogenesis and angiogenesis of pancreatic ductal adenocarcinoma by cooperating with MTA1/NuRD complex.
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Liu Xujun, Tuergong Abulaihaiti, Wang Mingzhen, Shi Weilong, Tian Xiaodong, Ting Xia, Cui Liyan, Si Wenzhe
Аннотация
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.
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.