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Stress Chaperones, Mortalin, and Pex19p Mediate 5-Aza-2' Deoxycytidine-Induced Senescence of Cancer Cells by DNA Methylation-Independent Pathway

¹ National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Japan.
² Department of Molecular and Cellular Physiology, University of Tsukuba, Japan.
³ Department of Chemistry and Biotechnology, School of Engineering, University of Tokyo, Japan.
⁴ Cellular and Molecular Biology Group, Department of Radiobiology, Institute for Environmental Sciences, Aomori, Japan.

Address correspondence to Sunil C. Kaul, PhD, National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1, Higashi, Tsukuba, Ibaraki, 305-8562, Japan. E-mail: s-kaul{at}aist.go.jp

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.