Histone acetyltransferase and histone deacetylase activities determine the acetylation status of histones, and have the ability to regulate gene expression through chromatin remodeling. A controlled balance between histone acetylation and histone deacetylation appears to be essential for normal cell growth. In cancer cells, some genes are repressed by inappropriate recruitment of histone deacetylases. The histone deacetylase inhibitors (HDACI) belong to the class of anticancer drugs that are effective in killing proliferating and non-proliferating tumor cells. In this review we discuss molecular mechanisms involved in the induction of cell cycle arrest, differentiation and induction of apoptosis in tumor cells by HDACI.
histone deacetylase inhibitors; apoptosis; cell cycle; chemotherapy
Beck GR Jr, Zerler B, Moran E: Gene array analysis of osteoblast differentiation. Cell Growth Differ 12:61-83, 2001.
Blagosklonny MV, Robey R, Sackett DL et al.: Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest and cytotoxicity. Mol Cancer Therap 11:937-941, 2002.
Burgess AJ, Pavey S, Warrener R et al.: Upregulation of 21waf1/CIP1 by histone deacetylase inhibitors reduces their cytotoxicity. Mol Pharmacol 60:828-837, 2001.
Burgess A, Ruefli A, Beamish H et al.: Histone deacetylase inhibitors specifically kill nonproliferating tumour cells. Oncogene 23:6693-6701, 2004.
Butler LM, Agus DB, Scher HI et al.: Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60:5165-5170, 2000.
Caron H, van Schaik B, van der Mee M et al.: The human transcriptome map: Clustering of highly expressed genes in chromosomal domains. Science 291:1289-1292, 2001.
Clausen MR: Butyrate and colorectal cancer in animals and in humans (mini-symposium: Butyrate and colorectal cancer). Eur J Cancer Prev 4:483-490, 1995.
Davie JR: Covalent modifications of histones: expression from chromatin templates. Curr Opin Genet Dev 8:173-178, 1998.
de Ruijter AJ, van Gennip AH, Caron HN et al.: Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737-749, 2003.
Glaser KB, Staver MJ, Waring JF et al.: Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors. Defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2:151-163, 2003.
Gottlicher M: Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol 83:S91-92, 2004.
Gottlicher M, Minucci S, Zhu P et al.: Valproic acid defines a novel class of HDAC inhibitors inducing differentiatiation of transformed cells. EMBO J 20:6969-6978, 2001.
Gui CY, Ngo L, Xu WS et al.: Histone deacetylase (HDAC) inhibitor activation of p21 WAF1 involves changes in promotor-associated proteins, including HDAC1. PNAS 101:1241-1246, 2004.
Jacobs R: Role of dietary factors in cell replication and colon cancer. Am J Clin Nutr 48(Suppl. 3):775-779, 1988.
Hofmanova J, Vaculova A, Kozubik A: Polyunsaturated fatty acids sensitize human colon adenocarcinoma HT-29 cells to death receptor-mediated apoptosis. Cancer Lett 218:33-41, 2005.
Kelly WK, Richon VM, O'Connor O et al.: Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 9:3578-3588, 2003.
Kim YK, Han JW, Woo YN et al.: Expression of p21 Waf1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3- kinase-PKCdelta signaling pathway. Oncogene 22:6023-6031, 2003.
Kuendgen A, Strupp C, Aivado M et al.: Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood 104:1266-1269, 2004.
Leskov KS, Klokov DY, Li J et al.: Synthesis and functional analyses of nuclear clusterin, a cell death protein. J Biol Chem 278:11590-11600, 2003.
Luo RX, Dean DC: Chromatin remodeling and transcriptional regulation. J Natl Cancer Inst 91:1288-1294, 1999.
Luger K, Richmond TJ: The histone tails of the nucleosome. Curr Opin Genet Dev 8:140-146, 1998.
McIntyre A, Gibson PR, Young GP: Butyrate production from dietary fibre and protection against large bowel cancer in a rat model. Gut 34:386-391, 1993.
Nebbioso A, Clarke N, Voltz E et al.: Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nature Med 11:77-84, 2005.
Qiu L, Burgess A, Fairlie DP et al.: Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. Mol Biol Cell 11:2069-2083, 2000.
Ragione FD, Criniti V, Pietra VD et al.: Genes modulated by histone acetylation as new effectors of butyrate activity. FEBS Lett 499:199-204, 2001.
Richon VM, Sandhoff TW, Rifkind RA et al.: Histone deacetylase inhibitor selectively induces p21 WAF1 expression and gene - associated histone acetylation. PNAS 97:10014-10019, 2000.
Rosato RR, Almenara JA, Yu C et al.: Simultaneous activation of the intrinsic and extrinsic pathways by HDAC inhibitors and TRAIL synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Mol Cancer Ther 2:1273-1284, 2003.
Rosato RR, Grant S: Histone deacetylase inhibitors in clinical development. Expert Opin Investig Drugs 13:21-38, 2004.
Rosato RR, Almenara JA,Yu C et al.: Evidence of a functional role for p21 WAF1/Cip1 down-regulation in synergistic antileukemic interactions between the histone deacetylase inhibitor sodium butyrate and flavopiridol. Mol Pharmacol 65:571-581, 2004.
Suenaga M, Soda H, Oka M et al.: Histone deacetylase inhibitors suppress telomerase reverse transcriptase mRNA expression in prostate cancer cells. Int J Cancer 97:621-625, 2002.
Vrana JA, Decker RH, Johnson CR et al.: Induction of apoptosis in U 937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. 0ncogene 18:7016-7025, 1999.
Warrell RP, He LZ, Richon V et al.: Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 90:1621-1925, 1998.
Wu JT, Archer SY, Hinnebusch B et al.: Transient vs. prolonged histone hyperacetylation: effects on colon cancer cell growth, differentiation, and apoptosis. Am J Physiol Gastrointest Liver Physiol 280:G482-G490, 2001.
Yoshida M, Kijima M, Akita M et al.: Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265:17174-17179, 1990.
Yoshida M, Furumai R, Nishiyama M et al.: Histone deacetylase as a new target for cancer chemotherapy. Cancer Chemother Pharmacol 48(Suppl. 11):20-26, 2001.
Sangshetti JN, Sakle NS, Dehghan MHG, Shinde DB. Histone deacetylases as targets for multiple diseases. Mini-Rev Med Chem. 13: 1005-1026, 2013.
Balakin KV, Ivanenkov YA, Kiselyov AS, Tkachenko SE. Histone deacetylase inhibitors in cancer therapy: Latest developments, trends and medicinal chemistry perspective. Anti-Cancer Agents Med Chem. 7: 576-592, 2007.
Rezacova M, Vavrova J, Vokurkova D, Zaskodova D. Effect of valproic acid and antiapoptotic cytokines on differentiation and apoptosis induction of human leukemia cells. General Phys Biophys. 25: 65-79, 2006.