A protein modification of TIGAR Fuels HCC Growth by Boosting Tumor Glucose Metabolism

Background & aims: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is characterized by profound metabolic reprogramming. TIGAR (TP53-induced glycolysis and apoptosis regulator) regulates glucose metabolism and redox balance by redirecting glucose flux toward the pentose phosphate pathway. Although TIGAR is frequently upregulated in HCC, the mechanisms controlling its activity remain poorly understood. We investigated whether SUMOylation regulates TIGAR function and HCC progression. Methods: TIGAR SUMOylation was evaluated in two independent HCC patient cohorts (n=86 and n=19), HCC cell lines and mouse models. Seahorse assays, metabolomic profiling, 13C-glucose tracing, mitochondrial analyses and in vivo tumor models were used to investigate its effects on glucose metabolism, oxidative stress and tumor growth. Results: TIGAR was found to be SUMOylated in HCC tissues, cultured cells and murine tumor models. SUMOylation enhanced the pro-tumorigenic activity of TIGAR by promoting its interaction with glycolytic enzymes, including PFKFB3 and HK2, resulting in increased glycolytic activity and pentose phosphate pathway flux. Conversely, SUMOylation-deficient K82R cells exhibited increased oxidative stress, mitochondrial dysfunction and reduced proliferation and invasion compared with WT TIGAR. In the orthotopic liver model (n=4 per group), K82R expression was associated with reduced tumor growth. In the CAM assay, SUMOylation-deficient K82R clones showed significantly reduced tumor weight (n=8 per group, p < 0.0001) and volume (n=4 per group, p < 0.05) compared with WT TIGAR cells. Conclusions: This study identifies Lys82 SUMOylation as a novel mechanism regulating TIGAR-mediated metabolic reprogramming and HCC progression. Targeting TIGAR SUMOylation may represent a novel therapeutic strategy for HCC. Impact and implications: This study identifies TIGAR SUMOylation as a new mechanism driving metabolic adaptation in hepatocellular carcinoma. SUMOylated TIGAR promotes glycolysis, pentose phosphate pathway activity and mitochondrial function. Loss of TIGAR SUMOylation increases oxidative stress and reduces tumor growth and invasion. These findings highlight TIGAR SUMOylation as a potential biomarker and therapeutic target in liver cancer. Overall, our data support targeting this pathway to improve therapeutic strategies for hepatocellular carcinoma.