American Association for Cancer Research
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Figure S5 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma

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journal contribution
posted on 2024-01-16, 08:21 authored by Pasquale Saggese, Aparamita Pandey, Martín Alcaraz, Eileen Fung, Abbie Hall, Jane Yanagawa, Erika F. Rodriguez, Tristan R. Grogan, Giorgio Giurato, Giovanni Nassa, Annamaria Salvati, Orian S. Shirihai, Alessandro Weisz, Steven M. Dubinett, Claudio Scafoglio

Figure S5


American Cancer Society (ACS)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Jonsson Comprehensive Cancer Center (JCCC)

Fondazione AIRC per la ricerca sul cancro ETS (AIRC)

Regione Campania

American-Italian Cancer Foundation (AICF)



Increased utilization of glucose is a hallmark of cancer. Sodium-glucose transporter 2 (SGLT2) is a critical player in glucose uptake in early-stage and well-differentiated lung adenocarcinoma (LUAD). SGLT2 inhibitors, which are FDA approved for diabetes, heart failure, and kidney disease, have been shown to significantly delay LUAD development and prolong survival in murine models and in retrospective studies in diabetic patients, suggesting that they may be repurposed for lung cancer. Despite the antitumor effects of SGLT2 inhibition, tumors eventually escape treatment. Here, we studied the mechanisms of resistance to glucose metabolism-targeting treatments. Glucose restriction in LUAD and other tumors induced cancer cell dedifferentiation, leading to a more aggressive phenotype. Glucose deprivation caused a reduction in alpha-ketoglutarate (αKG), leading to attenuated activity of αKG-dependent histone demethylases and histone hypermethylation. The dedifferentiated phenotype depended on unbalanced EZH2 activity that suppressed prolyl-hydroxylase PHD3 and increased expression of hypoxia-inducible factor 1α (HIF1α), triggering epithelial-to-mesenchymal transition. Finally, a HIF1α-dependent transcriptional signature of genes upregulated by low glucose correlated with prognosis in human LUAD. Overall, this study furthers current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying targets to prevent the development of resistance to therapies targeting glucose metabolism. Epigenetic adaptation allows cancer cells to overcome the tumor-suppressive effects of glucose restriction by inducing dedifferentiation and an aggressive phenotype, which could help design better metabolic treatments.

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