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

Oncogene volume 41, pages 2651–2662 (2022)Cite this article

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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 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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Fig. 1: Epigenetic regulation of metabolism in human mesothelioma cells.
Fig. 2: G6PD is repressed by its promoter H3K9me3 deposition in human mesothelioma cells.
Fig. 3: Inhibition of histone methylation induces human mesothelioma cell apoptosis.
Fig. 4: Aerobic glycolysis and G6PD do not maintain human mesothelioma cell survival in vitro.
Fig. 5: G6PD increases ROS promotion to regulate ROS-regulated cell death pathway to promote human mesothelioma cell death in vitro.
Fig. 6: G6PD is not essential for human mesothelioma survival in vitro and in vivo.
Fig. 7: Pharmacological activation of G6PD enzymatic activity suppresses human mesothelioma growth in vivo.

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Acknowledgements

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).

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Authors and Affiliations

  1. School of Life Sciences, Tianjin University, Tianjin, 300072, China

    Chunwan Lu

  2. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, 30912, USA

    Chunwan Lu, Dafeng Yang, John D. Klement & Kebin Liu

  3. Georgia Cancer Center, Medical College of Georgia, Augusta, GA, 30912, USA

    Dafeng Yang, John D. Klement, Zhuoqi Liu, Huidong Shi, Han-Fei Ding & Kebin Liu

  4. Charlie Norwood VA Medical Center, Augusta, GA, 30904, USA

    Dafeng Yang, John D. Klement & Kebin Liu

  5. Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Yolonda L. Colson

  6. Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, 27402, USA

    Nicholas H. Oberlies

  7. Mycosynthetix, Inc, Hillsborough, NC, 27278, USA

    Cedric J. Pearce

  8. Ionic Pharmaceuticals, Brookline, MA, 02445, USA

    Aaron H. Colby & Mark W. Grinstaff

  9. Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA

    Aaron H. Colby & Mark W. Grinstaff

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Contributions

CL, YLC, NHO, CJP, AHC, MWG, HS, HD, and KL designed the study and wrote or reviewed the manuscript. NHO and CJP provided key study materials. CL, DY, JDK, performed experiments, collected data, and analyzed data. ZL and HS performed bioinformatics analysis and data analysis.

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Correspondence to Chunwan Lu or Kebin Liu.

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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

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