SENP1 drives glycolysis and cisplatin resistance in gastric cancer via desumoylating ENO1.

Background: Gastric cancer remains a leading cause of cancer-related mortality in world, with advanced-stage patients facing poor prognosis despite emerging therapies. SUMOylation modification is a major post-translation modification, which is essential for cellular behaviors. However, the potential function of SUMOylation in gastric cancer (GC) and the underlying molecular mechanisms remain unclear.

Methods: In our study, a bioinformatics analysis was conducted to screen potential regulators within the SUMO-Specific Peptidase (SENP) family in GC. In vitro functional experiments including CCK8, colony formation, transwell assay, sphere formation, Glycolytic flux, ECAR and OCR and several animal models including GC xenografts, organoids and lung metastasis models were employed to ascertain the role of SENP1 in GC progression and metastasis. Mass spectrometry analysis, coimmunoprecipitation and immunofluorescence staining were performed to elucidate the mechanisms by which SENP1 functions in GC cells.

Results: We identified that SENP1 was upregulated in GC tissues and correlated with a poor prognosis. Multiple functional experiments demonstrated that SENP1 promotes the proliferation, migration, stemness and glycolysis of GC cells. Mechanistically, SENP1 binds to α-enolase (ENO1) and deSUMOylates the SUMO sites (K256, K394) of SUMO2-modified ENO1, enhancing ENO1 stability and drive gastric tumorigenesis. Meanwhile, SENP1 inhibitor Momordin Ιc (Mc) in combination with cisplatin has a synergistic effect on gastric tumor growth in vitro and in vivo.

Conclusion: SENP1 facilitates gastric cancer progression by metabolic reprogramming. Targeting SENP1 with Momordin Ic is a novel therapeutic approach for GC patients.