Abstract
DNA demethylating agents are used to reverse epigenetic silencing of tumor suppressors in cancer therapeutics. Understanding of the molecular and cellular factors involved in DNA demethylation-induced gene desilencing and senescence is still limited. We have tested the involvement of two stress chaperones, Pex19p and mortalin, in 5-Aza-2' deoxycytidine (5AZA-dC; DNA demethylating agent)-induced senescence. We found that the cells overexpressing these chaperones were highly sensitive to 5AZA-dC, and their partial silencing eliminated 5AZA-dC-induced senescence in human osteosarcoma cells. We demonstrate that these chaperones modulate the demethylation and chromatin remodeling-dependent (as accessed by p16(INK4A) expression) and remodeling-independent (such as activation of tumor suppressor p53 pathway) senescence response of cells. Furthermore, we found the direct interactions of 5AZA-dC with these chaperones that may alter their functions. We conclude that both mortalin and Pex19p are important mediators, prognostic indicators, and tailoring tools for 5AZA-dC-induced senescence in cancer cells.
MeSH terms
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Antimetabolites, Antineoplastic / pharmacology*
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Azacitidine / analogs & derivatives*
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Azacitidine / pharmacology
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Biomarkers / analysis
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Biomarkers, Tumor / analysis
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Cell Line, Tumor
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Cellular Senescence / drug effects*
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Chromatin / drug effects
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Chromatin Assembly and Disassembly / drug effects
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Cyclin-Dependent Kinase Inhibitor p16 / drug effects
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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DNA Methylation / drug effects*
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DNA Modification Methylases / antagonists & inhibitors*
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Decitabine
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Epigenesis, Genetic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Gene Silencing / drug effects
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Genes, p53 / genetics
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HSP70 Heat-Shock Proteins / genetics
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HSP70 Heat-Shock Proteins / pharmacology*
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / pharmacology*
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Humans
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Lipoproteins / genetics
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Lipoproteins / pharmacology*
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Membrane Proteins / genetics
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Membrane Proteins / pharmacology*
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Molecular Chaperones / genetics
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Molecular Chaperones / pharmacology*
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Osteosarcoma / pathology*
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Tumor Suppressor Proteins / drug effects
Substances
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Antimetabolites, Antineoplastic
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Biomarkers
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Biomarkers, Tumor
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Chromatin
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Cyclin-Dependent Kinase Inhibitor p16
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HSP70 Heat-Shock Proteins
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Heat-Shock Proteins
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Lipoproteins
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Membrane Proteins
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Molecular Chaperones
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Tumor Suppressor Proteins
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mortalin
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PEX19 protein, human
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Decitabine
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DNA Modification Methylases
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Azacitidine