SENP1 drives glycolytic reprogramming to promote malignant progression of gastric cancer via deSUMOylation of HIF-1α

Objective: Sentrin/SUMO-specific protease 1 (SENP1), a key deSUMOylating enzyme, stabilizes hypoxia-inducible factor 1-alpha (HIF-1α) to promote tumor aerobic glycolysis. This study aims to determine whether SENP1 drives malignant progression in gastric Cancer (GC) through glycolytic reprogramming.

Methods: SENP1 and HIF-1α expression levels and their association with patient prognosis were analyzed using the GEPIA2.0 database. Clinical GC tissues were collected, and mRNA/protein expression levels were measured. SENP1 knockdown and overexpression models were established. Malignant phenotypes and glycolytic flux were assessed. SENP1-HIF-1α interaction and SUMOylation levels were determined. A subcutaneous xenograft model in nude mice was used for in vivo validation.

Results: SENP1 was upregulated in GC tissues and correlated with poor overall survival. SENP1 knockdown suppressed GC cell proliferation, colony formation, migration, and invasion, while promoting Apoptosis. Conversely, SENP1 overexpression exerted opposing effects. Moreover, SENP1 depletion reduced glycolytic activity, as indicated by decreased glucose uptake, lactate release, ATP content, and expression of key glycolytic genes. Treatment with DMOG, which stabilizes HIF-1α, partially restored glycolytic activity and mitigated the malignant phenotypes driven by SENP1 knockdown. In vivo, SENP1 silencing impeded tumor growth and downregulated expression of HIF-1α, Ki-67, and key glycolytic genes.

Conclusion: SENP1 may de‑SUMOylate HIF-1α, thereby driving glycolysis and malignant progression in GC cells. The SENP1‑HIF‑1α axis may play an important role in the metabolic reprogramming of GC, indicating that this axis could be a promising target for future metabolic interventions.