Deubiquitinase OTUD4 Stabilizes SLC5A2 to Promote Pancreatic Cancer Proliferation and Migration Through Enchaining Glycolysis‐Mediated Autophagy

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by its insidious onset, rapid progression, and poor treatment outcomes. Sodium glucose transporter 2 (SLC5A2) is the predominant sodium‐glucose transporter. Our study reveals that SLC5A2 interacted with ovarian tumor family deubiquitinase 4 (OTUD4) to stabilize and increase its expression in PDAC. SLC5A2 overexpression promoted pancreatic cancer cell proliferation in vitro and in vivo, while also promoting cell migration, invasion, and autophagy. Conversely, SLC5A2 knockdown reversed these effects. RNA‐seq and GSEA revealed that glycolysis pathway activation was inhibited following SLC5A2 knockdown. Consistent with this, qRT‐PCR and western blot analyses indicated reduced glycolysis‐related gene expression levels. Metabolomics further revealed that knockdown of SLC5A2 decreased intermediate product levels in glycolysis, as well as glucose intake. Glycolysis inhibitor (2‐DG) amplified the effect of SLC5A2 knockdown in promoting autophagy, resulting in decreased pancreatic cancer proliferation, migration, and invasion. Notably, the antitumor effects of SLC5A2 knockdown were reversed by Bafilomycin A1. Additionally, treatment with the SLC5A2 inhibitor, canagliflozin (CANA), inhibited pancreatic cancer growth by inhibiting glycolysis and enhancing autophagy in vitro/vivo. These findings suggest that SLC5A2 promotes pancreatic cancer progression by regulating the glycolysis‐autophagy axis, suggesting it as a therapeutic target for improving PDAC treatment outcomes.