2. Academic Validation
  3. SENP1 drives glycolysis and cisplatin resistance in gastric cancer via desumoylating ENO1

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

  • J Exp Clin Cancer Res. 2025 Oct 8;44(1):285. doi: 10.1186/s13046-025-03543-z.
Yuan Fang # 1,  Yunru Gu # 1,  Tingting Xu # 1,  Peng Wang # 2,  Xi Wu 3,  Haoyang Shen 1,  Yangyue Xu 1,  Zixiang Xu 1,  Lei Cao 4,  Xiao Li 5,  Hao Wu 6,  Yongqian Shu 7 8,  Pei Ma 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
  • 2 Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
  • 3 Department of Oncology, Wuxi People's Hospital, Wuxi Medical Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Nanjing Medical University, Wuxi, 214000, China.
  • 4 Department of Oncology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, 223800, Jiangsu, China.
  • 5 Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. ilixiao@126.com.
  • 6 Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China. whdactor@njmu.edu.cn.
  • 7 Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China. yongqian_shu@163.com.
  • 8 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China. yongqian_shu@163.com.
  • 9 Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China. mapei@njmu.edu.cn.
  • 10 Department of Oncology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, 223800, Jiangsu, China. mapei@njmu.edu.cn.
  • 11 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China. mapei@njmu.edu.cn.
  • 12 Department of Oncology, Jiangsu Province Hospital Jurong Branch, Zhenjiang, 212400, Jiangsu, China. mapei@njmu.edu.cn.
  • # Contributed equally.
PMID: 41063235 DOI: 10.1186/s13046-025-03543-z
Abstract

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.

Keywords

Cisplatin; Gastric cancer; Glycolysis; SENP1; SUMOylation.

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