Glucose deprivation promotes de-differentiation in lung adenocarcinoma

Increased utilization of glucose is a hallmark of cancer. Several studies are investigating the efficacy of glucose restriction on solid cancers, by glucose transporter blocking or glycolysis inhibition. However, the adaptations of cancer cells to glucose restriction are not known. Here, we report the discovery that glucose restriction in lung adenocarcinoma (LUAD) cells induces de-differentiation, leading to a more aggressive phenotype. Glucose deprivation causes a reduction in alpha-ketoglutarate (aKG), leading to attenuated activity of aKG-dependent histone demethylases and consequent histone hypermethylation. We further show that this de-differentiated and aggressive phenotype depends on unbalanced EZH2 activity, causing inhibition of prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1a (HIF1a). Finally, we identified an HIF1a-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further our knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying novel targets to prevent the development of resistance to metabolic therapies targeting glucose uptake and glycolysis.