Sirtuin 2 Regulates Histone Glycation as a Semi-deglycase

Methylglyoxal (MGO) and glyoxal (GO) are reactive carbonyl species (RCS) generated as side products in glycolysis and carbohydrate, protein, and fat catabolism, which are enriched in most cancer cells. MGO/GO-induced nonenzymatic glycation on histones plays pathophysiologically important roles in regulating the three-dimensional architecture of cellular chromatin and cancer development. In our previous studies, we have uncovered that enzymes DJ-1 and PAD4 exhibit "glyoxalase" and "deglycase" activities to antagonize the MGO/GO-modifications of histones. We also found that the general inhibition of histone deacetylases using suberoylanilide hydroxamic acid (SAHA) antagonized histone MGO-glycation due to the direct competition of reactive sites (i.e., lysine residues). Here, we report that a histone deacetylase, sirtuin 2 (SIRT2), functions as a "semi-deglycase" that removes lactic and glycolic acids from ε-<i>N</i>-l-lactyllysine and hydroxyacetyllysine residues, which are derived from MGO/GO-lysine adducts through the isomerization catalyzed by DJ-1. Overall, SIRT2 is a newly identified regulator for histone glycation, which can prevent the cytotoxicity of MGO and GO by eventually converting them into lactate and glycolate with the assistance of an enzymatically inactive DJ-1 mutant (i.e., DJ-1-C106A).