Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner
Abstract
Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell–specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation. Nucleus-translocated Transferrin interacts with PPARα and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPARα-associated Transferrin upregulates iron-dependent PHD2-mediated PPARα P87 hydroxylation and subsequently disrupts the binding of MDM2 to PPARα, therefore inhibiting MDM2-mediated PPARα ubiquitination and degradation. Reconstitution of Transferrin S685A and NLS mutation or knock-in expression of PPARα P87A inhibited PPARα-mediated FAO upon energy stress, enhanced HCC cell apoptosis, and impeded liver tumor growth in mice. Importantly, combined treatment with Transferrin pS685 blocking peptide suppressing AMPK-Transferrin-PPARα axis could synergize with a well-established AMPK activator Metformin to inhibit tumor growth. Additionally, Transferrin pS685-mediated PPARα P87 hydroxylation is positively correlated with PPARα expression levels in human HCC specimens and poor patient prognosis. These findings revealed a mechanism by which Transferrin can sense energy stress to promote the hydroxylation and protein stability of PPARα through iron-dependent activation of PHD2 and underscore the moonlighting function of Transferrin in lipid catabolism and liver tumor development.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (32)
Xu Qian
Department of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences
Qimin Zhou
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Yuan Ouyang
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine
Xiaohong Wu
Xue Sun
MOE Engineering Research Center for Electrochemical Energy Storage and Carbon Neutrality in Cold Regions
Shuo Wang
Yuran Duan
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Zhiqiang Hu
State Key Laboratory of Fine Chemical, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, School of Chemical Engineering
Yueru Hou
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Zheng Wang
Xiaohan Chen
Department of Chemical and Biomolecular Engineering
Katherine L. Wang
St. Agnes Academy
Yuli Shen
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Bofei Dong
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Yanni Lin
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Ting Wen
Center for High Pressure Science and Technology Advanced Research (HPSTAR)
Qi Tian
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Zhanpeng Guo
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Min Li
Liwei Xiao
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Qingang Wu
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Ying Meng
Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences
Guijun Liu
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Hangjie Ying
Department of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences
Yahui Zhou
Department of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences
Wuchang Zhang
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine
Shengzhong Duan
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province
Xueli Bai
Tong Liu
Peng Zhan
Zhimin Lu
Daqian Xu
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine