Ceramide synthases (CerSs) catalyze the formation of ceramides from sphingoid bases and acyl-CoA substrates. Increasing evidence suggests that cancer cells generally exhibit altered sphingolipid metabolism in the tumorigenesis of multiple cancers. However, there is no evidence that CerSs are associated with pancreatic ductal carcinoma (PDAC). In the present study, we examined CerS expression in clinical tissue and conducted data mining to investigate the clinical significance of CerSs in the TCGA-PAAD database. We found that high CerS6 expression positively correlated with progression and predicted worse prognosis in PDAC patients, establishing CerS6 as a potential biomarker for PDAC. Furthermore, CerS6 promoted cell proliferation, colony formation and invasion by producing C16-ceramide and was required for tumor formation. Mechanistically, AKT1 interacted with and phosphorylated FOXP3 at S418, which decreased the binding of FOXP3 to the CERS6 promoter and in turn induced CerS6 expression by reconstituting an activated state on the CERS6 promoter. The AKT1/FOXP3 axis mediated the CerS6 expression and promoted p53 mutant pancreatic tumorigenesis by producing excessive C16-ceramide, which induced the accumulation of mutant p53. Thus, our study explores the relationship between PI3K/AKT signaling and sphingolipid metabolism, revealing an oncogenic role for CerS6, which may represent a potential target for PDAC treatment.

神经酰胺合酶 (CerSs) 催化从鞘氨醇碱基和酰基辅酶 A 底物形成神经酰胺。越来越多的证据表明，癌细胞在多种癌症的肿瘤发生过程中通常表现出改变的鞘脂代谢。然而，没有证据表明 CerSs 与胰腺导管癌 (PDAC) 相关。在本研究中，我们检测了临床组织中 CerS 的表达，并进行了数据挖掘，以研究 TCGA-PAAD 数据库中 CerSs 的临床意义。我们发现高 CerS6 表达与进展呈正相关，并预测 PDAC 患者的预后较差，从而将 CerS6 确立为 PDAC 的潜在生物标志物。此外，CerS6 通过产生 C16-神经酰胺促进细胞增殖、集落形成和侵袭，并且是肿瘤形成所必需的。机械地，CERS6启动子，进而通过在CERS6启动子上重建激活状态来诱导 CerS6 表达。AKT1/FOXP3 轴介导 CerS6 表达，并通过产生过量的 C16-神经酰胺促进 p53 突变胰腺肿瘤发生，从而诱导突变 p53 的积累。因此，我们的研究探索了 PI3K/AKT 信号传导与鞘脂代谢之间的关系，揭示了 CerS6 的致癌作用，这可能代表 PDAC 治疗的潜在目标。