Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
State Key Laboratory of Systems Medicine for Cancer, Institute for Personalized Medicine and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Nat Commun. 2023 Nov 21;14(1):7572. doi: 10.1038/s41467-023-43378-w.
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.
多囊肾病（PKD）患者发生肾透明细胞癌（ccRCC）的风险很高，ccRCC 是一种脂质代谢失调的恶性肿瘤。SET 结构域包含蛋白 2（SETD2）已被确定为 ccRCC 中的重要肿瘤抑制因子和免疫抑制剂。然而，SETD2 在 PKD 中导致 ccRCC 发生的作用在很大程度上仍未得到探索。在此，我们在 SETD2 缺失诱导的 PKD-ccRCC 转化小鼠模型中进行了代谢组学、脂质组学、转录组学和蛋白质组学分析。我们的分析表明，SETD2 缺失导致广泛的代谢重编程事件，最终导致鞘磷脂生物合成增强和肿瘤发生。临床 ccRCC 患者标本进一步证实了代谢重编程和鞘磷脂积累的异常。鞘氨醇合酶抑制剂米诺环素可缓解 Setd2 敲除引起的肿瘤症状，米诺环素是丝氨酸棕榈酰转移酶和鞘磷脂生物合成的选择性抑制剂。我们的结果表明，SETD2 缺乏在 PKD-ccRCC 转化过程中促进大规模代谢重编程和鞘磷脂生物合成。本研究介绍了高质量的多组学资源，并揭示了 SETD2 在肿瘤发生过程中对脂质代谢的调控机制。
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