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

Hanyu Rao, Changwei Liu, Aiting Wang, Chunxiao Ma, Yue Xu, Tianbao Ye, Wenqiong Su, Peijun Zhou, Wei-Qiang Gao, Li Li () and Xianting Ding ()
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Hanyu Rao: Shanghai Jiao Tong University
Changwei Liu: Shanghai Jiao Tong University
Aiting Wang: Shanghai Jiao Tong University
Chunxiao Ma: Shanghai Jiao Tong University
Yue Xu: Shanghai Jiao Tong University
Tianbao Ye: Shanghai Jiao Tong University
Wenqiong Su: Shanghai Jiao Tong University
Peijun Zhou: Shanghai Jiao Tong University
Wei-Qiang Gao: Shanghai Jiao Tong University
Li Li: Shanghai Jiao Tong University
Xianting Ding: Shanghai Jiao Tong University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43378-w

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