@article{273aba4044534bd6bbf704e724a95004,
title = "Loss of tyrosine catabolic enzyme HPD promotes glutamine anaplerosis through mTOR signaling in liver cancer",
abstract = "The liver plays central roles in coordinating different metabolic processes, such as the catabolism of amino acids. In this study, we identify a loss of tyrosine catabolism and a concomitant increase in serum tyrosine levels during liver cancer development. Liver cells with disordered tyrosine catabolism, as exemplified by the suppression of a tyrosine catabolic enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), display augmented tumorigenic and proliferative potentials. Metabolomics profiling and isotope tracing reveal the metabolic reliance of HPD-silenced cells on glutamine, coupled with increased tricarboxylic acid cycle metabolites and their associated amino acid pools. Mechanistically, HPD silencing reduces ketone bodies, which regulate the proliferative and metabolic phenotypes via the AMPK/mTOR/p70S6 kinase pathway and mTOR-dependent glutaminase (GLS) activation. Collectively, our results demonstrate a metabolic link between tyrosine and glutamine metabolism, which could be exploited as a potentially promising anticancer therapy for liver cancer.",
keywords = "glutamine metabolism, HPD, liver cancer, mTOR signaling, tyrosine catabolism",
author = "Man Tong and Wong, {Tin Lok} and Hongzhi Zhao and Yuanyuan Zheng and Xie, {Yu Nong} and Li, {Cheuk Hin} and Lei Zhou and No{\'e}lia Che and Yun, {Jing Ping} and Kwan Man and Lee, {Terence Kin Wah} and Zongwei Cai and Stephanie Ma",
note = "Funding Information: We thank the Centre for PanorOmic Sciences-Imaging & Flow Cytometry Core (The University of Hong Kong) for providing and maintaining the equipment and technical support needed for flow cytometric analysis and imaging microscopy. We also thank the Department of Pathology (The University of Hong Kong) for help with histology service, the Centre for Comparative Medicine Research (The University of Hong Kong) for supporting our animal studies, and the Department of Applied Biology and Chemical Technology (The Hong Kong Polytechnic University) for providing equipment for Seahorse studies. We thank Dr. Xin Chen (University of California, San Francisco) for sharing of plasmids used for hydrodynamic tail vein injection. We thank Dr. Meritxell Huch (The Gurdon Institute, University of Cambridge) for sharing of HCC organoids. This work was supported in part by grants from The University of Hong Kong-Seed Fund for Basic Research for New Staff (201909185038) and Seed Fund for Basic Research (202011159194) and Research Grants Council of Hong Kong-Collaborative Research Fund (C7026-18G). The graphical abstract was created with BioRender.com. M.T. and S.M. conceived the project and designed the experiments. Z.C. H.Z.Z. and Y.Y.Z. designed and carried out all MS-related experiments. M.T. performed the experiments with assistance from T.-L.W. Y.-N.X. C.-H.L. L.Z. N.C. and T.K.-W.L. K.M. and J.-P.Y. consented the patients and provided clinical samples and clinical data information. M.T. S.M. and Z.C. provided funding support and supervised the project. M.T. and S.M. wrote the manuscript. The authors declare no competing interests. Funding Information: We thank the Centre for PanorOmic Sciences-Imaging & Flow Cytometry Core (The University of Hong Kong) for providing and maintaining the equipment and technical support needed for flow cytometric analysis and imaging microscopy. We also thank the Department of Pathology (The University of Hong Kong) for help with histology service, the Centre for Comparative Medicine Research (The University of Hong Kong) for supporting our animal studies, and the Department of Applied Biology and Chemical Technology (The Hong Kong Polytechnic University) for providing equipment for Seahorse studies. We thank Dr. Xin Chen (University of California, San Francisco) for sharing of plasmids used for hydrodynamic tail vein injection. We thank Dr. Meritxell Huch (The Gurdon Institute, University of Cambridge) for sharing of HCC organoids. This work was supported in part by grants from The University of Hong Kong-Seed Fund for Basic Research for New Staff ( 201909185038 ) and Seed Fund for Basic Research ( 202011159194 ) and Research Grants Council of Hong Kong-Collaborative Research Fund ( C7026-18G ). The graphical abstract was created with BioRender.com . Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = aug,
day = "24",
doi = "10.1016/j.celrep.2021.109617",
language = "English",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}
