The glycolytic-based metabolism of cancers promotes an acidic microenvironment that is responsible for increased aggressiveness. However, the effects of acidosis on tumour metabolism have been almost unexplored, and the metabolic adaptation of cancer cells to acidosis has never been compared with the metabolic response of normal cells.

In this study, to pinpoint for the first time the different metabolic profiles between osteosarcoma (OS) cells and normal human fibroblasts (Fb) under short-term acidosis, we used capillary electrophoresis with time-of-flight mass spectrometry (CE-TOFMS). We also screened alterations of the epigenetic profiles – DNA methylation and histone acetylation – of OS cells and compared it with those of normal Fb.

Using CE-TOFMS, we observed a significant metabolic difference associated with glycolysis repression (dihydroxyacetone phosphate), increase of amino acid catabolism (phosphocreatine and glutamate) and urea cycle enhancement (arginino succinic acid) in OS cells compared with normal Fb. Noteworthy, metabolites associated with chromatin modification, like UDP-glucose and N⁸-acetylspermidine, decreased more in OS cells than in normal Fb. Further, combined bisulfite restriction analysis (COBRA) and acetyl-H3 immunoblotting indicated an epigenetic stability in OS cells than in normal Fb, and OS cells were more sensitive to an HDAC inhibitor under acidosis than under neutral condition.

Our data suggest that acidosis promotes a metabolic reprogramming that can contribute to the epigenetic maintenance under acidosis only in OS cells, and then the acidic microenvironment should be considered for future therapeutic approaches. The application of epigenetic modulators will be able to become an effectively therapeutic option to selectively target malignancies under the acidic microenvironment.