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. Significance: 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.

Cancer cells utilize larger amounts of glucose than their normal counterparts, and the expression of GLUT transporters is a known diagnostic target and a prognostic factor for many cancers. Recent evidence has shown that sodium-glucose transporters are also expressed in different types of cancer, and SGLT2 has raised particular interest because of the current availability of anti-diabetic drugs that block SGLT2 in the kidney, which could be readily re-purposed for the treatment of cancer. The aim of this article is to perform a narrative review of the existing literature and a critical appraisal of the evidence for a role of SGLT2 inhibitors for the treatment and prevention of cancer. SGLT2 inhibitors block Na-dependent glucose uptake in the proximal kidney tubules, leading to glycosuria and the improvement of blood glucose levels and insulin sensitivity in diabetic patients. They also have a series of systemic effects, including reduced blood pressure, weight loss, and reduced inflammation, which also make them effective for heart failure and kidney disease. Epidemiological evidence in diabetic patients suggests that individuals treated with SGLT2 inhibitors may have a lower incidence and better outcomes of cancer. These studies are confirmed by pre-clinical evidence of an effect of SGLT2 inhibitors against cancer in xenograft and genetically engineered models, as well as by in vitro mechanistic studies. The action of SGLT2 inhibitors in cancer can be mediated by the direct inhibition of glucose uptake in cancer cells, as well as by systemic effects. In conclusion, there is evidence suggesting a potential role of SGLT2 inhibitors against different types of cancer. The most convincing evidence exists for lung and breast adenocarcinomas, hepatocellular carcinoma, and pancreatic cancer. Several ongoing clinical trials will provide more information on the efficacy of SGLT2 inhibitors against cancer.

Nutrient deprivation causes dedifferentiation in solid tumors, driving an aggressive phenotype. We previously showed that glucose starvation-induced dedifferentiation is driven by epigenetic changes induced by a deficit of alpha-ketoglutarate (α-KG). Deficient activity of α-KG-dependent histone demethylases leads to unbalanced hypermethylation of histone 3 on lysine 27 (H3K27) by methyltransferase EZH2. H3K27 hypermethylation is a key mechanism of starvation-induced dedifferentiation. Here, we investigate a new aspect of this mechanism and show that epitranscriptomic changes are also induced by glucose restriction. Specifically, hypermethylation of select long non-coding RNAs leads to their upregulation under glucose deprivation as a consequence of reduced activity of the RNA demethylase FTO. We identified LINC00662 as an lncRNA required for EZH2 recruitment to target gene promoters induced by low glucose. These findings characterize the epigenetic response to glucose restriction beyond histone methylation, revealing that RNA methylation of lncRNAs such as LINC00662 represents a parallel mechanism converging on EZH2.

Table S6 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma

Table S5 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma

Table S5 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma