Loss of tyrosine catabolic enzyme HPD promotes glutamine anaplerosis through mTOR signaling in liver cancer

Man Tong, Tin Lok Wong, Hongzhi Zhao, Yuanyuan Zheng, Yu Nong Xie, Cheuk Hin Li, Lei Zhou, Noélia Che, Jing Ping Yun, Kwan Man, Terence Kin Wah Lee, Zongwei Cai, Stephanie Ma

Research output: Journal article publicationJournal articleAcademic researchpeer-review

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.

Original languageEnglish
Article number109617
JournalCell Reports
Volume36
Issue number8
DOIs
Publication statusPublished - 24 Aug 2021

Keywords

  • glutamine metabolism
  • HPD
  • liver cancer
  • mTOR signaling
  • tyrosine catabolism

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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