Downregulation of JMJD2a and LSD1 is involved in CK2 inhibition-mediated cellular senescence through the p53-SUV39h1 pathway
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Lysine methylation is one of the most important histone modificationsthat modulate chromatin structure. In the present study,the roles of the histone lysine demethylases JMJD2a and LSD1in CK2 downregulation-mediated senescence were investigated. The ectopic expression of JMJD2a and LSD1 suppressed the inductionof senescence-associated β-galactosidase activity andheterochromatin foci formation as well as the reduction of colony-forming and cell migration ability mediated by CK2 knockdown. CK2 downregulation inhibited JMJD2a and LSD1 expressionby activating the mammalian target of rapamycin (mTOR)-ribosomal p70 S6 kinase (p70S6K) pathway. In addition, the downregulationof JMJD2a and LSD1 was involved in activating thep53-p21Cip1/WAF1-SUV39h1-trimethylation of the histone H3 Lys9(H3K9me3) pathway in CK2-downregulated cells. Further, CK2downregulation-mediated JMJD2a and LSD1 reduction was foundto stimulate the dimethylation of Lys370 on p53 (p53K370me2)and nuclear import of SUV39h1. Therefore, this study indicatedthat CK2 downregulation reduces JMJD2a and LSD1 expressionby activating mTOR, resulting in H3K9me3 induction by increasingthe p53K370me2-dependent nuclear import of SUV39h1. These results suggest that CK2 is a potential therapeutic targetfor age-related diseases.
Abstract
Lysine methylation is one of the most important histone modificationsthat modulate chromatin structure. In the present study,the roles of the histone lysine demethylases JMJD2a and LSD1in CK2 downregulation-mediated senescence were investigated. The ectopic expression of JMJD2a and LSD1 suppressed the inductionof senescence-associated β-galactosidase activity andheterochromatin foci formation as well as the reduction of colony-forming and cell migration ability mediated by CK2 knockdown. CK2 downregulation inhibited JMJD2a and LSD1 expressionby activating the mammalian target of rapamycin (mTOR)-ribosomal p70 S6 kinase (p70S6K) pathway. In addition, the downregulationof JMJD2a and LSD1 was involved in activating thep53-p21Cip1/WAF1-SUV39h1-trimethylation of the histone H3 Lys9(H3K9me3) pathway in CK2-downregulated cells. Further, CK2downregulation-mediated JMJD2a and LSD1 reduction was foundto stimulate the dimethylation of Lys370 on p53 (p53K370me2)and nuclear import of SUV39h1. Therefore, this study indicatedthat CK2 downregulation reduces JMJD2a and LSD1 expressionby activating mTOR, resulting in H3K9me3 induction by increasingthe p53K370me2-dependent nuclear import of SUV39h1. These results suggest that CK2 is a potential therapeutic targetfor age-related diseases.
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