NFYA promotes the anti-tumor effects of gluconeogenesis in hepatocellular carcinoma through the regulation of PCK1 expression

Abstract

Reprogramming of glucose metabolism occurs in many human tumor types, and one of these, gluconeogenesis, is known to exhibit anti-tumor effects in hepatocellular carcinoma (HCC). The transcription factor NFYA regulates gluconeogenesis in the normal liver tissue, but the function of the NFYA-gluconeogenesis axis in cancer and the functional differences of NFYA splicing variants in the regulation of gluconeogenesis is still unclear. Here, we demonstrate that NFYAv2, the short-form variant, upregulates the transcription of a gluconeogenic enzyme PCK1. We further reveal that its regulation induces high ROS levels and energy crisis in HCC and promotes cell death. These indicate that the NFYAv2-gluconeogenesis axis has enhanced anti-tumor effects in HCC, suggesting that the axis may be a potential therapeutic target for HCC. Furthermore, Nfyav1-deficient mice, spontaneously overexpressing Nfyav2, had no increasing gluconeogenesis in the liver. Taken together, our results reveal NFYAv2-gluconeogenesis axis has anti-tumor effects and the potential for NFYAv2 to be a safer therapeutic target for HCC.

Identification of subclusters and prognostic genes based on glycolysis/gluconeogenesis in hepatocellular carcinoma

“…In HCC, the process of glycolysis is often dysregulated and leads to increased glucose consumption and lactate production ( 37 ). Gluconeogenesis then exhibits anti-tumor effects in hepatocellular carcinoma ( 38 ). This study showed that several metabolic pathways were activated in HCC and may plays a significant role in HCC development and progression.…”

Schisantherin A inhibits cell proliferation by regulating glucose metabolism pathway in hepatocellular carcinoma

“…Studies have shown that glucose metabolism disorder is a representative metabolic feature in HCC ( Tsujimoto et al, 2022 ). An increase in the degree of glycolysis in tumors occurs to meet the energy demands of rapidly proliferating tumor cells, and glycolysis can also produce intermediate metabolites supporting the biosynthesis of nucleotides, amino acids, and lipids, thus allowing the rapid proliferation of tumor cells ( Feng et al, 2020 ).…”