Abstract 3033: Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity

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Abstract Lung cancer is the most frequent cancer-related cause of death, and adenocarcinoma (LUAD) is the most frequent type. Despite the recent success of immunotherapies, survival of lung cancer patients has not significantly improved in the last decades. New therapies are necessary. We have previously identified sodium-glucose transporter 2 (SGLT2) as the major responsible for glucose uptake in LUAD, and we have showed that treatment with SGLT2 inhibitors significantly delays LUAD development and prolongs survival in murine models. However, our data shows that SGLT2 inhibitors also induce de-differentiation of LUAD cells, leading to a more aggressive phenotype and increased resistance to cisplatin. Glucose deprivation causes reduced αKG levels, leading to reduced activity of αKG-dependent histone demethylases and consequent histone hypermethylation. Supplementation of αKG or inhibition of the histone methyltransferase EZH2 reverse this phenotype, suggesting that this de-differentiated phenotype depends on insufficiency of αKG-dependent histone demethylases and unbalanced EZH2 activity. Consistently, double treatment with an SGLT2 inhibitor and an EZH2 inhibitor significantly reduces the tumor burden in a genetically engineered murine model of LUAD. We further characterized the effect of low glucose-induced tumor de-differentiation, identifying stabilization of hypoxia inducible factor 1α (HIF1α) as a major pathway responsible for the acquisition of a more aggressive phenotype following glucose deprivation. Finally, we identified an HIF1α-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 nutrient deprivation and identifying novel targets to prevent the development of resistance to metabolic therapies. Citation Format: Pasquale Saggese, Aparamita Pandey, Eileen Fung, Giorgio Giurato, Alessandro Weisz, Steven M. Dubinett, Claudio Scafoglio. Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3033.