title: Stress chaperones, mortalin, and pex19p mediate 5-aza-2' deoxycytidine-induced senescence of cancer cells by DNA methylation-independent pathway.
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.
authors: National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1, Higashi, Tsukuba, Ibaraki, Japan.
authors: Nashi
authors: N
authors: Widodo
authors: Custer C
authors: CC
authors: Deocaris
authors: Kamaljit
authors: K
authors: Kaur
authors: Kamrul
authors: K
authors: Hasan
authors: Tomoko
authors: T
authors: Yaguchi
authors: Kazuhiko
authors: K
authors: Yamasaki
authors: Takashi
authors: T
authors: Sugihara
authors: Tetsuro
authors: T
authors: Ishii
authors: Renu
authors: R
authors: Wadhwa
authors: Sunil C
authors: SC
authors: Kaul
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D002843:Chromatin / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects; D016158:Genes, p53 / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000494:pharmacology*; D018832:Molecular Chaperones / Q000235:genetics / Q000494:pharmacology*; D012516:Osteosarcoma / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D014408:Biomarkers, Tumor; D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008074:Lipoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D025521:Tumor Suppressor Proteins; C080352:mortalin; C087343:PEX19 protein, human; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine