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 pathways, 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.
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We thank Dr. Roni Bollag at the Georgia Cancer Center Biorepository for providing the human mesothelioma specimen and for pathological analysis. We also thank Dr. Natasha Savage for tumor specimen analysis and Dr. Kimya Jones for immunohistochemical analysis of tumor specimen. This work was supported by the National Cancer Institute grants R01 CA227433 (to MWG, YLC, NHO, KL), R01CA133085 (to KL), P01 CA125066 (to NHO), R01CA190429, and R01CA236890 (to H-FD), F30CA236436 (to JDK), and the US Department of Veterans Affairs Award CX001364 (to KL).
AHC, MWG, and NHO have ownership interest in Ionic Pharmaceuticals, LLC. KL has an ownership interest in CheMedImmune Inc. NHO is a member of the Scientific Advisory Board of Mycosynthetix, Inc. CJP has an ownership interest in Mycosynthetix, Inc. Other authors have declared that no conflict of interest exists.
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Lu, C., Yang, D., Klement, J.D. et al. H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth. Oncogene 41, 2651–2662 (2022). https://doi.org/10.1038/s41388-022-02283-0