Abstract
In cancer cells, the expression level of histone deacetylase (HDAC), a well known epigenetic regulator, is abnormally increased resulting in the inhibition of their target tumor suppressor genes. Treatment of HDAC inhibitors to the cancer cells induces rebound of tumor suppressor genes expressions followed by cellular senescence or apoptosis. Based on this mode of action against cancer cells, a number of HDAC inhibitors have been developed as anti-cancer therapeutics. However, considering that HDACs exist ubiquitously in normal cells and have important roles in the maintaining homeostasis and biological activity, the effects of HDAC inhibitors on normal cells need to be evaluated in detail. Here, we discuss the general characteristics of HDACs, HDAC inhibitors and their effects on the mesenchymal stem cell (MSC), an adult stem cell with normal diploidy comparing with the effects on cancer cells.
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References
Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K (2009) The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev 23:1171–1176
Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenfuhr M, Maertens G, Banck M, Zhou MM, Walsh MJ, Peters G, Gil J (2009) Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev 23:1177–1182
Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW, Hiebert SW (2008) Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell 30:61–72
Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784
Bommi PV, Dimri M, Sahasrabuddhe AA, Khandekar J, Dimri GP (2010) The polycomb group protein BMI1 is a transcriptional target of HDAC inhibitors. Cell Cycle 9:2663–2673
Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Monch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K (2007) The polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 21:525–530
Cho HH, Park HT, Kim YJ, Bae YC, Suh KT, Jung JS (2005) Induction of osteogenic differentiation of human mesenchymal stem cells by histone deacetylase inhibitors. J Cell Biochem 96:533–542
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840
Chung SY, Hill WE, Doty P (1978) Characterization of the histone core complex. Proc Natl Acad Sci U S A 75:1680–1684
Dokmanovic M, Clarke C, Marks PA (2007) Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 5:981–989
Dovey OM, Foster CT, Cowley SM (2010) Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation. Proc Natl Acad Sci U S A 107:8242–8247
Eickbush TH, Moudrianakis EN (1978) The histone core complex: an octamer assembled by two sets of protein-protein interactions. Biochemistry 17:4955–4964
Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23
Grunstein M (1997) Histone acetylation in chromatin structure and transcription. Nature 389:349–352
Gui CY, Ngo L, Xu WS, Richon VM, Marks PA (2004) Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A 101:1241–1246
Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42
Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636
Jiang H, Ju Z, Rudolph KL (2007) Telomere shortening and ageing. Z Gerontol Geriatr 40:314–324
Jung JW, Lee S, Seo MS, Park SB, Kurtz A, Kang SK, Kang KS (2010) Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3. Cell Mol Life Sci 67:1165–1176
Kouzarides T (2000) Acetylation: a regulatory modification to rival phosphorylation? EMBO J 19:1176–1179
Kretsovali A, Hadjimichael C, Charmpilas N (2012) Histone deacetylase inhibitors in cell pluripotency, differentiation, and reprogramming. Stem Cells Int 2012:184154
Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299–1307
Lagace DC, Nachtigal MW (2004) Inhibition of histone deacetylase activity by valproic acid blocks adipogenesis. J Biol Chem 279:18851–18860
Lee S, Park JR, Seo MS, Roh KH, Park SB, Hwang JW, Sun B, Seo K, Lee YS, Kang SK, Jung JW, Kang KS (2009) Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells. Cell Prolif 42:711–720
Lee S, Jung JW, Park SB, Roh K, Lee SY, Kim JH, Kang SK, Kang KS (2011) Histone deacetylase regulates high mobility group A2-targeting microRNAs in human cord blood-derived multipotent stem cell aging. Cell Mol Life Sci 68:325–336
Marks PA, Xu WS (2009) Histone deacetylase inhibitors: potential in cancer therapy. J Cell Biochem 107:600–608
Olovnikov AM (1996) Telomeres, telomerase, and aging: origin of the theory. Exp Gerontol 31:443–448
Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111
Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A 97:10014–10019
Valentini A, Gravina P, Federici G, Bernardini S (2007) Valproic acid induces apoptosis, p16INK4A upregulation and sensitization to chemotherapy in human melanoma cells. Cancer Biol Ther 6:185–191
Wilting RH, Yanover E, Heideman MR, Jacobs H, Horner J, van der Torre J, DePinho RA, Dannenberg JH (2010) Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis. EMBO J 29:2586–2597
Xu WS, Parmigiani RB, Marks PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26:5541–5552
Yan W, Liu S, Xu E, Zhang J, Zhang Y, Chen X (2012) Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8. Oncogene. [Epub ahead of print]
Yang XJ, Seto E (2008) The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 9:206–218
Zhou R, Han L, Li G, Tong T (2009) Senescence delay and repression of p16INK4a by Lsh via recruitment of histone deacetylases in human diploid fibroblasts. Nucleic Acids Res 37:5183–5196
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Lee, S., Jung, JW., Kang, KS. (2013). Histone Deacetylase Inhibitor Induces Replicative Senescence of Mesenchymal Stem Cells. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Volume 1. Tumor Dormancy and Cellular Quiescence and Senescence, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5958-9_17
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DOI: https://doi.org/10.1007/978-94-007-5958-9_17
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