Abstract
Abstract Tyrosine, like other amino acids, is the building block for proteins as well as an alternative energy source for cellular functions. Liver is the major organ where tyrosine degradation takes place to produce intermediates or precursors for gluconeogenesis and ketogenesis. In normal liver, tyrosine can be converted to fumarate and acetoacetate through multiple steps of enzymatic reactions. In patients with liver cancer, an upregulation of serum tyrosine levels has been previously reported, suggesting a deregulated tyrosine catabolism in liver cancer. In this study, we observed a significant down-regulation of the five enzymes involved in tyrosine catabolism (TAT, HPD, HGD, GSTZ1 and FAH) in tumor samples compared with normal liver samples from TCGA database. Further, downregulation of the first three enzymes significantly correlates with overall and disease-free survival in liver cancer patients. Downregulation of these enzymes is also confirmed in a separate liver cancer patient transcriptome cohort of Asian ethnicity, as well as at the proteomic level by both Western blot and immunohistochemistry assays. Our group has previously reported that downregulation of the first tyrosine catabolizing enzyme TAT (tyrosine aminotransferase) could promote liver tumorigenesis. Here, we further investigate if reprogrammed tyrosine metabolism could promote cancer development by modulating gene expression and activity of the second enzyme HPD (4-hydroxyphenylpyruvate dioxygenase) in the tyrosine catabolism pathway. We found blocking HPD gene expression or its enzymatic activity could promote cell proliferation and tumor formation in liver cancer. This could be partially attributed to enhanced mitochondrial respiratory capacity accompanied with reduction in ROS level, NADP/NADPH ratio and DNA damage. Conversely, overexpression of HPD led to an opposing effect. Taken together, this study reveals an unreported alteration of tyrosine metabolism which drives cancer development in liver cancer. Citation Format: Man Tong, Tin Lok Wong, Steve Tin-Chi Luk, Noelia Che, Xin Yuan Guan, Yun Fei Yuan, Terence Kin-Wah Lee, Stephanie Ma. Deranged tyrosine metabolism drives tumorigenesis in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1432.
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