Dysregulated glucuronic acid metabolism exacerbates hepatocellular carcinoma progression and metastasis through the TGFß signalling pathway.

ABSTRACT

BACKGROUND: Glucuronic acid metabolism participates in cellular detoxification, extracellular matrix remodeling and cell adhesion and migration. Here, we aimed to explore the crosstalk between dysregulated glucuronic acid metabolism and crucial metastatic signalling in glutathione S-transferase zeta 1 (GSTZ1)-deficient hepatocellular carcinoma (HCC). METHODS: Transwell, HCC xenograft and Gstz1-/- mouse models were used to examine the role of GSTZ1 in HCC metastasis. Non-targeted and targeted metabolomics and global transcriptomic analyses were performed to screen significantly altered metabolic and signalling pathways in GSTZ1 overexpressing hepatoma cells. Further, RNA-binding protein immunoprecipitation, Biotin-RNA pull-down, mRNA decay assays and luciferase reporter assays were used to explore the interaction between RNA and RNA-binding proteins. RESULTS: GSTZ1 was universally silenced in both human and murine HCC cells, and its deficiency contributed to HCC metastasis in vitro and in vivo. UDP-glucose 6-dehydrogenase (UGDH)-mediated UDP-glucuronic acid (UDP-GlcUA) accumulation promoted hepatoma cell migration upon GSTZ1 loss. UDP-GlcUA stabilized TGFßR1 mRNA by enhancing its binding to polypyrimidine tract binding protein 3, contributing to the activation of TGFß/Smad signalling. UGDH or TGFßR1 blockade impaired HCC metastasis. In addition, UGDH up-regulation and UDP-GlcUA accumulation correlated with increased metastatic potential and decreased patient survival in GSTZ1-deficient HCC. CONCLUSIONS: GSTZ1 deficiency and subsequent up-regulation of the glucuronic acid metabolic pathway promotes HCC metastasis by increasing the stability of TGFßR1 mRNA and activating TGFß/Smad signalling. UGDH and a key metabolite, UDP-GlcUA, may serve as prognostic markers. Targeting UGDH might be a promising strategy for HCC therapy.