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SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer

Author

Listed:
  • Hanyu Rao

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Changwei Liu

    (Shanghai Jiao Tong University)

  • Aiting Wang

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Chunxiao Ma

    (Shanghai Jiao Tong University)

  • Yue Xu

    (Shanghai Jiao Tong University)

  • Tianbao Ye

    (Shanghai Jiao Tong University
    Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Wenqiong Su

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Peijun Zhou

    (Shanghai Jiao Tong University)

  • Wei-Qiang Gao

    (Shanghai Jiao Tong University)

  • Li Li

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Xianting Ding

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

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.

Suggested Citation

  • Hanyu Rao & Changwei Liu & Aiting Wang & Chunxiao Ma & Yue Xu & Tianbao Ye & Wenqiong Su & Peijun Zhou & Wei-Qiang Gao & Li Li & Xianting Ding, 2023. "SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43378-w
    DOI: 10.1038/s41467-023-43378-w
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