2. Academic Validation
  3. DEPDC1 as a metabolic target regulates glycolysis in renal cell carcinoma through AKT/mTOR/HIF1α pathway

DEPDC1 as a metabolic target regulates glycolysis in renal cell carcinoma through AKT/mTOR/HIF1α pathway

  • Cell Death Dis. 2024 Jul 27;15(7):533. doi: 10.1038/s41419-024-06913-1.
Si-Chen Di # 1,  Wen-Jin Chen # 1 2,  Wei Yang # 1,  Xiang-Min Zhang # 3,  Ke-Qin Dong 1 4,  Yi-Jun Tian 5,  Ye Sun 6,  Cheng Qian 7,  Jia-Xin Chen 1,  Zi-Chang Liu 1,  Zi-Xuan Gong 1,  Jian Chu 8,  Wang Zhou 9,  Xiu-Wu Pan 10,  Xin-Gang Cui 11
Affiliations

Affiliations

  • 1 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
  • 2 Department of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, China.
  • 3 Department of Urology, Shanghai Baoshan Luodian Hospital, Shanghai, China.
  • 4 Department of Urology, Chinese PLA General Hospital of Central Theater Command, Wuhan, China.
  • 5 Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 6 Department of Urology, Taian 88 Hospital, Taian, Shandong, China.
  • 7 Department of Urology, Shanghai Pudong New Area Gongli Hospital, Shanghai, China.
  • 8 Department of Urology, Shanghai Baoshan Luodian Hospital, Shanghai, China. doctor_chu@126.com.
  • 9 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. brilliant212@163.com.
  • 10 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. panxiuwu@126.com.
  • 11 Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. cuixingang@xinhuamed.com.cn.
  • # Contributed equally.
PMID: 39068164 DOI: 10.1038/s41419-024-06913-1
Abstract

Renal cell carcinoma (RCC) is considered a "metabolic disease" characterized by elevated glycolysis in patients with advanced RCC. Tyrosine kinase inhibitor (TKI) therapy is currently an important treatment option for advanced RCC, but drug resistance may develop in some patients. Combining TKI with targeted metabolic therapy may provide a more effective approach for patients with advanced RCC. An analysis of 14 RCC patients (including three needle biopsy samples with TKI resistance) revealed by sing-cell RNA Sequencing (scRNA-seq) that glycolysis played a crucial role in poor prognosis and drug resistance in RCC. TCGA-KIRC and glycolysis gene set analysis identified DEPDC1 as a target associated with malignant progression and drug resistance in KIRC. Subsequent experiments demonstrated that DEPDC1 promoted malignant progression and glycolysis of RCC, and knockdown DEPDC1 could reverse TKI resistance in RCC cell lines. Bulk RNA Sequencing (RNA-seq) and non-targeted metabolomics Sequencing suggested that DEPDC1 may regulate RCC glycolysis via Akt/mTOR/HIF1α pathway, a finding supported by protein-level analysis. Clinical tissue samples from 98 RCC patients demonstrated that DEPDC1 was associated with poor prognosis and predicted RCC metastasis. In conclusion, this multi-omics analysis suggests that DEPDC1 could serve as a novel target for TKI combined with targeted metabolic therapy in advanced RCC patients with TKI resistance.

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