Abstract
Although cancer cells are frequently faced with a nutrient- and oxygen-poor microenvironment, elevated hexosamine-biosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anticancer strategy. The gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) is downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low-glucose conditions. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo uridine triphosphate synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc synthesis for elevated O-GlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-L-norleucine blocked HBP-mediated O-GlcNAcylation and suppressed tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation.
Highlights
Gaining insight into the fundamental role of metabolic reprogramming in cancer has contributed immensely to our understanding of tumorigenesis and cancer progression [1]
phosphoenolpyruvate carboxykinase 1 (PCK1) did not change the mRNA or protein expression levels of OGT, OGA, and Glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), the key enzymes involved in regulating O-GlcNAcylation and hexosaminebiosynthesis pathway (HBP) (Supplemental Figure 1, E–N)
It remains unknown whether gluconeogenesis contributes to maintaining HBP-mediated O-GlcNAcylation in cancer cells under low nutrient conditions [5]
Summary
Gaining insight into the fundamental role of metabolic reprogramming in cancer has contributed immensely to our understanding of tumorigenesis and cancer progression [1]. Nutrient limitations (such as glucose deprivation) in solid tumors may require cancer cells to exhibit the metabolic flexibility required to sustain proliferation and survival [2, 3]. Gluconeogenesis (the pathway opposite to glycolysis) operates during starvation and occurs mainly in the liver, and plays key roles in metabolic reprogramming, cancer cell plasticity, and tumor growth [5, 6]. Several key gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase 1 (PCK1, known as PEPCK-C), fructose-1,6-bisphosphatase, and glucose-6-phosphatase, were previously found to be dysregulated in several types of cancer, including hepatocellular carcinoma (HCC) [7]. The oncogenic or tumor suppressor roles of PCK1 in different types of human cancers are rather controversial. The underlying mechanism determining its aberrant expression and altered function in multiple types of tumors remains incompletely understood
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