H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth

Abstract

The role of glucose-6-phosphate dehydrogenase (G6PD) in human cancer is incompletely understood. In a metabolite screening, we observed that inhibition of H3K9 methylation suppressed aerobic glycolysis and enhances the PPP in human mesothelioma cells. Genome-wide screening identified G6PD as an H3K9me3 target gene whose expression is correlated with increased tumor cell apoptosis. Inhibition of aerobic glycolysis enzyme LDHA and G6PD had no significant effects on tumor cell survival. Ablation of G6PD had no significant effect on human mesothelioma and colon carcinoma xenograft growth in athymic mice. However, activation of G6PD with the G6PD-selective activator AG1 induced tumor cell death. AG1 increased tumor cell ROS production and the resultant extrinsic and intrinsic death pathway, mitochondrial processes, and unfolded protein response in tumor cells. Consistent with increased tumor cell death in vitro, AG1 suppressed human mesothelioma xenograft growth in a dose-dependent manner in vivo. Furthermore, AG1 treatment significantly increased tumor-bearing mouse survival in an intra-peritoneum xenograft athymic mouse model. Therefore, in human mesothelioma and colon carcinoma, G6PD is not essential for tumor growth. G6PD acts as a metabolic checkpoint to control metabolic flux towards the PPP to promote tumor cell apoptosis, and its expression is repressed by its promotor H3K9me3 deposition.

Targeting Aurora-A inhibits tumor progression and sensitizes thyroid carcinoma to Sorafenib by decreasing PFKFB3-mediated glycolysis

“…Our work demonstrated PFKFB3 is a novel substrate of Aurora-A, and a major determinant for Aurora-A-induced cancer progression. To our knowledge, our study uncovered a novel mechanism of Aurora-A as an oncogene to promote tumor cell glycolysis and The advantages of accelerated glycolytic flux in tumors remain controversial [30,31]. Our data suggested that PFKFB3-regulated glycolysis can promote the proliferation and invasion of TC cells by enhancing the energy supply, an important mechanism of Aurora-Amediated TC cell progression.…”

Targeting Aurora-A Inhibits Tumor Progression and Sensitizes Thyroid Carcinoma to sorafenib by decreasing PFKFB3-mediated glycolysis

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Metabolic signatures and potential biomarkers in the progression of type 2 diabetes mellitus with cognitive impairment patients: a cross-sectional study

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