唾液酸转移酶ST3GAL4通过调节内质网应激和线粒体稳态，指导一种双重机制来促进胰腺导管腺癌进展。

Sialyltransferase ST3GAL4 directs a dual mechanism to promote pancreatic ductal adenocarcinoma progression by regulating endoplasmic reticulum stress and mitochondrial homeostasis.

作者信息

Zeng Jiayue, Liu Yijing, Dong Chenfei, Chong Suli, Liu Yang, Bian Ziming, Chen Xiaoming, Fan Sairong

机构信息

Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China; Institute of Glycobiological Engineering, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.

出版信息

Biochim Biophys Acta Mol Basis Dis. 2025 Aug;1871(6):167900. doi: 10.1016/j.bbadis.2025.167900. Epub 2025 May 15.

DOI:10.1016/j.bbadis.2025.167900

PMID:40381815

Abstract

BACKGROUND

Pancreatic ductal adenocarcinoma (PDAC) exhibits a highly aggressive solid malignancy characterized by dismal prognosis and limited therapeutic strategies. Emerging evidence underscores that aberrant hypersialylation exists in PDAC, and suggests that it is closely associated with the pathophysiological alterations of PDAC. ST3GAL4, one of the sialyltransferases catalyzing the α2,3-sialylation of glycans, has been found to be significantly overexpressed in PDAC. Nevertheless, its role and underlying mechanisms driving malignant progression of PDAC remain unexplored.

METHODS

The oncogenic potential of ST3GAL4 in facilitating the proliferation and metastasis of PDAC cells was assessed through phenotypic analysis. Subsequently, we investigated the mechanistic interplay between ST3GAL4 and endoplasmic reticulum stress (ERS)-driven PDAC cell death using the lectin blotting, co-immunoprecipitation, and Western blotting assays. Additionally, electron microscopy, confocal microscopy, and Western blotting assays were performed to investigate the association between ST3GAL4 and mitochondrial-related cell death in PDAC.

RESULTS

Our study identifies ST3GAL4 overexpression significantly promotes PDAC cell proliferation and metastasis by systematically upregulating global cellular sialylation. Meanwhile, knockdown of ST3GAL4 reduces the sialylation level of PRKR-like ER kinase (PERK) and increases its phosphorylation, which in turn activates the PERK-eIF2α-ATF4 signaling pathway and ultimately induces ERS-related PDAC cell death. Furthermore, ST3GAL4 suppression interferes with the ER-to-mitochondrial Ca flux and induces VDAC1 oligomerization, eventually triggering mitochondrial-associated reprogrammed cell death in PDAC.

CONCLUSION

The overexpression of ST3GAL4 modulates ER stress and mitochondrial homeostasis within PDAC via hypersialylation, which may offer a new insight into the potential therapeutic strategy for PDAC.

摘要

背景

胰腺导管腺癌（PDAC）是一种极具侵袭性的实体恶性肿瘤，预后不佳且治疗策略有限。新出现的证据强调，PDAC中存在异常的高唾液酸化现象，并表明其与PDAC的病理生理改变密切相关。ST3GAL4是催化聚糖α2,3-唾液酸化的唾液酸转移酶之一，已发现在PDAC中显著过表达。然而，其在PDAC恶性进展中的作用及潜在机制仍未被探索。

方法

通过表型分析评估ST3GAL4在促进PDAC细胞增殖和转移方面的致癌潜力。随后，我们使用凝集素印迹、免疫共沉淀和蛋白质印迹分析，研究了ST3GAL4与内质网应激（ERS）驱动的PDAC细胞死亡之间的机制相互作用。此外，进行了电子显微镜、共聚焦显微镜和蛋白质印迹分析，以研究ST3GAL4与PDAC中线粒体相关细胞死亡之间的关联。

结果

我们的研究发现，ST3GAL4的过表达通过系统性上调整体细胞唾液酸化，显著促进PDAC细胞增殖和转移。同时，敲低ST3GAL4可降低蛋白激酶R样内质网激酶（PERK）的唾液酸化水平并增加其磷酸化，进而激活PERK-eIF2α-ATF4信号通路，最终诱导与ERS相关的PDAC细胞死亡。此外，抑制ST3GAL4会干扰内质网到线粒体的钙通量并诱导电压依赖性阴离子通道1（VDAC1）寡聚化，最终引发PDAC中与线粒体相关的程序性细胞死亡。