Sotagliflozin, a Dual SGLT1/2 Inhibitor, Modulates DNMT1 and Class I/II HDAC Expression in Association With Anticancer Effects in Breast and Lung Cancer Cells

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Sodium-glucose cotransporter (SGLT) inhibitors are increasingly recognised for anticancer activity beyond their established glycaemic effects. While selective SGLT2 inhibitors have been reported to suppress tumour cell proliferation and modulate AMPK/mTOR and PI3K/AKT signalling, whether dual SGLT1/2 inhibition is associated with modulation of epigenetic regulators has remained largely unexplored. Here, we investigated the anticancer effects of sotagliflozin, a dual SGLT1/2 inhibitor, in breast (MCF-7) and lung (A549) cancer cells. Sotagliflozin reduced cell viability, clonogenic survival, migration, and invasion, and these effects were accompanied by G2/M cell-cycle arrest, increased AMPK activation, and changes in PTEN-AKT-mTOR signalling. Molecular docking analysis predicted favourable interactions between sotagliflozin and DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), with the strongest predicted binding to DNMT1 (-8.9 kcal/mol). Consistent with these computational predictions, sotagliflozin treatment was associated with reduced total DNMT enzymatic activity, decreased DNMT1 mRNA and protein abundance, and reduced protein abundance of class I and class II histone deacetylases (HDAC1-4 and HDAC6) in both cell lines. In addition, sotagliflozin treatment was associated with autophagy-related changes, including increased acidic vesicular organelles together with elevated LC3-II and Beclin-1 protein abundance. Collectively, these findings demonstrate that sotagliflozin exerts broad anticancer effects in breast and lung cancer cells and provide preliminary evidence that its treatment is associated with modulation of DNMT1 and HDAC expression. Further studies are required to determine whether these epigenetic changes contribute directly to the observed cellular responses or represent downstream consequences of metabolic perturbation.

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