SUV39H2/KMT1B Inhibits the cardiomyocyte senescence phenotype by down-regulating BTG2/PC3.

Suppressor of variegation 3-9 homolog 2 (SUV39H2/KMT1B), a member of the SUV39 subfamily of lysine methyltransferases (KMTs), functions as an oncogene in various types of cancers. Here, we demonstrate a novel function of SUV39H2 that drives the cardiomyocyte aging process through BTG2. In our study, cardiomyocyte aging was induced by H2O2 and aging cells exhibited increases in SUV39H2. Knockdown of SUV39H2 accelerated cardiomyocyte senescence, while overexpression of SUV39H2 inhibited the cardiomyocyte senescence phenotype. These effects of SUV39H2 on cardiomyocytes were independent of DNA damage and mitochondrial dysfunction. Interestingly, RNA sequencing and bioinformatics analyses identified a strong correlation between SUV39H2 and BTG2. In addition to this, BTG2 protein levels were significantly increased in SUV39H2-deficient cardiomyocytes, and BTG2 knockdown virtually rescued the cardiomyocyte senescence phenotype induced by SUV39H2 knockdown. Taken together, these results indicate that SUV39H2 protects cardiomyocytes from H2O2 exposure-induced oxidative stress, DNA damage, and mitochondrial dysfunction by regulating the p53-BTG2 pathway. Our findings provide evidence that the activation of SUV39H2 has therapeutic or preventive potential against cardiac aging.