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

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. [Display omitted] •Loss of HPD promotes cell proliferation and hepatic tumorigenesis•HPD silencing promotes glutamine anaplerosis through mTOR activation•Co-targeting p70S6 kinase and glutaminase suppresses hepatic tumors with loss of HPD•Loss of HPD is predictive of the response to combined metabolic therapy Tong et al. report that deranged tyrosine catabolism can predict poor prognosis in human liver cancer. Loss of tyrosine catabolic enzyme HPD promotes glutamine dependency and supports hepatic tumorigenesis, which could be exploited as a metabolic vulnerability for liver cancer treatment.