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SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer
Hanyu Rao1,2, Changwei Liu2, Aiting Wang1,2
1Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
Patients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain-containing 2 (SETD2) has been identified as an important tumor suppressor and an immunosuppressor in ccRCC. However, the role of SETD2 in ccRCC generation in PKD remains largely unexplored. Herein, we perform metabolomics, lipidomics, transcriptomics and proteomics within SETD2 loss induced PKD-ccRCC transition mouse model. Our analyses show that SETD2 loss causes extensive metabolic reprogramming events that eventually results in enhanced sphingomyelin biosynthesis and tumorigenesis. Clinical ccRCC patient specimens further confirm the abnormal metabolic reprogramming and sphingomyelin accumulation. Tumor symptom caused by Setd2 knockout is relieved by myriocin, a selective inhibitor of serine-palmitoyl-transferase and sphingomyelin biosynthesis. Our results reveal that SETD2 deficiency promotes large-scale metabolic reprogramming and sphingomyelin biosynthesis during PKD-ccRCC transition. This study introduces high-quality multi-omics resources and uncovers a regulatory mechanism of SETD2 on lipid metabolism during tumorigenesis.
Insights
Loss of SETD2 in polycystic kidney disease (PKD) promotes clear cell renal cell carcinoma (ccRCC) by altering lipid metabolism, specifically enhancing sphingomyelin production. This finding offers new insights into ccRCC development in PKD patients.
Area of Science:
- Oncology
- Metabolomics
- Genetics
Background:
- Polycystic kidney disease (PKD) patients have an increased risk of clear cell renal cell carcinoma (ccRCC).
- SET domain-containing 2 (SETD2) acts as a tumor suppressor and immunosuppressor in ccRCC, but its role in PKD-associated ccRCC is unclear.
Purpose of the Study:
- To investigate the role of SETD2 in ccRCC development within the context of PKD.
- To explore the impact of SETD2 loss on metabolic reprogramming and lipid metabolism during PKD-ccRCC transition.
Main Methods:
- Utilized a mouse model with SETD2 loss to study PKD-ccRCC transition.
- Conducted multi-omics analyses including metabolomics, lipidomics, transcriptomics, and proteomics.
- Analyzed clinical ccRCC patient specimens.
Main Results:
- SETD2 loss induced significant metabolic reprogramming, leading to increased sphingomyelin biosynthesis and tumorigenesis.
- Abnormal metabolic reprogramming and sphingomyelin accumulation were confirmed in human ccRCC samples.
- Inhibition of sphingomyelin biosynthesis using myriocin alleviated tumor symptoms in the Setd2 knockout model.
Conclusions:
- SETD2 deficiency drives metabolic reprogramming and sphingomyelin biosynthesis in PKD-ccRCC transition.
- This study provides valuable multi-omics data and elucidates SETD2's regulatory role in lipid metabolism during tumorigenesis.
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