Decreased SLC27A5 Suppresses Lipid Synthesis and Tyrosine Metabolism to Activate the Cell Cycle in Hepatocellular Carcinoma

Abstract

Tyrosine is an essential ketogenic and glycogenic amino acid for the human body, which means that tyrosine is not only involved in protein metabolism, but also participates in the metabolism of lipids and carbohydrates. The liver is an important place for metabolism of lipids, carbohydrates, and proteins. The metabolic process of biological macro-molecules is a basis for maintaining the physiological activities of organisms, but the cross-linking mechanism of these processes is still unclear. Here, we found that the tyrosine-metabolizing enzymes, which were specifically and highly expressed in the liver, were significantly down-regulated in hepatocellular carcinoma (HCC), and had a correlation with a poor prognosis of HCC patients. Further analysis found that the reduction of tyrosine metabolism would activate the cell cycle and promote cell proliferation. In addition, we also found that the solute carrier family 27 member 5 (SLC27A5) regulates the expression of tyrosine-metabolizing enzymes through nuclear factor erythroid 2-related factor 2 (NRF2). Therefore, the SLC27A5 and tyrosine-metabolizing enzymes that we have identified coordinate lipid and tyrosine metabolism, regulate the cell cycle, and are potential targets for cancer treatment.

Metabolomics profiling of AKT/c-Met-induced hepatocellular carcinogenesis and the inhibitory effect of Cucurbitacin B in mice

“…The tyrosine metabolic pathway is a crucial part of biological processes that is involved in making neurotransmitters, hormones, and melanin. Previous studies have shown that the end products of this metabolic pathway are involved in lipid biosynthesis, implying crosstalk between metabolite-mediated tyrosine and lipid metabolism ( Wang J. et al, 2022 ). The results suggest that the pathogenic changes occurring in the formative stage of HCC in mice predominantly included lipid metabolism, amino acid metabolism, and glucose metabolism.…”

“…Moreover, tyrosine is produced by the conversion of phenylalanine through phenylalanine, tyrosine and tryptophan biosynthesis. Previous research has demonstrated a substantial association between the malfunction of tyrosine metabolic pathways and liver cancer ( Wang J. et al, 2022 ). Fumaric acid and acetoacetate, which are the end products of tyrosine metabolism, can be converted to acetyl-CoA, which is involved in lipid biosynthesis.…”

Biological function analysis of ARHGAP39 as an independent prognostic biomarker in hepatocellular carcinoma

“…We know that not only the cell cycle [45], but also metabolic pathways, play a role in the progression of hepatocellular carcinoma [46,47]. For example, reduced tyrosine metabolism activates the cell cycle and promotes cell proliferation [48], and enzymes involved in glycolysis, such as Pyruvate kinase-Pyruvate kinase M2 (PKM2), are highly expressed and are strongly related to a bad OS in HCC [46]. Besides, the LinkOmics dataset identified the key roles of ARHGAP39 in the cell cycle, hippo signaling pathway, spliceosome, and RNA transport.…”

Tyrosine metabolic reprogramming coordinated with the tricarboxylic acid cycle to drive glioma immune evasion by regulating PD‐L1 expression

“…Furthermore, HPD is also a prognostic predictor and a potential therapeutic target in breast cancer 34 . Surprisingly, tyrosine metabolism was significantly downregulated in liver and kidney cancers, which in turn activated the cell cycle and promoted tumor progression 35,36 . The refractory glioma is largely due to the heterogeneity of the tumor, so identifying the subtype of glioma has guiding significance for its clinical treatment.…”