The histone deacetylase inhibitor trichostatin A induces cell cycle arrest and rapid upregulation of gadd45β in LS174T human colon cancer cells

DOI: 10.4236/abc.2012.21005   PDF   HTML     4,077 Downloads   8,501 Views   Citations


Histone deacetylase (HDAC) inhibitors are considered as promising therapeutic agents against several malignant diseases because they inhibit cancer cell proliferation. The stress sensor genes of the growth arrest and DNA damage-inducible protein (gadd45) family exhibit disordered expression in several types of malignant diseases and are thus a novel target for cancer therapy. However, there have been only few investigations of whether HDAC inhibitors affect the expression of gadd45 genes. We examined the effects of a HDAC inhibitor, trichostatin A (TSA), on the time-dependent expression of gadd45 genes in the human colon cancer cell line LS174T. Addition of TSA to LS174T cells induced inhibition of cell proliferation by arresting the cell cycle. We found that TSA treatment of LS174T cells induced rapid upregulation of gadd45β mRNA expression within 15 min, reaching a peak level at 3 h. Although the time-dependent expression pattern of gadd45β mRNA was similar to that of gadd45β mRNA, the peak level of gadd45β was lower than that of gadd45β. TSA treatment also upregulated the mRNA level of p21Waf1/Cip1, a prolif- eration inhibitor, after 3 h, but downregulated the mRNA levels of cyclin D1, a proliferation inducer, after 3 h, and of c-Myc after 1 h. TSA treatment induced a certain level of apoptosis, but the mRNA level of p53, a potent apoptosis inducer, was down-regulated after 3 h. These results suggest that the up-regulation of p21Waf1/Cip1 and apoptosis was independent of p53 and that the early upregulation of gadd45β gene, which precedes the upregulation of p21Waf1/Cip1 and the downregulation of cyclin D1, are important in TSA-treated LS174T cells.

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Taniguchi, T. , Iwashita, J. , Murata, J. , Ueda, K. and Abe, T. (2012) The histone deacetylase inhibitor trichostatin A induces cell cycle arrest and rapid upregulation of gadd45β in LS174T human colon cancer cells. Advances in Biological Chemistry, 2, 43-50. doi: 10.4236/abc.2012.21005.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] [1] Berger, S.L. (2007) The complex language of chromatin regulation during transcription. Nature, 447, 407-412. doi:10.1038/nature05915
[2] Hess-Stumpp, H., Bracker, T.U., Henderson, D. and Po- litz, O. (2007) MS-275, a potent orally available inhibitor of histone deacetylases—The development of an anti can- cer agent. The International Journal of Biochemistry & Cell Biology, 39, 1388-1405. doi:10.1016/j.biocel.2007.02.009
[3] Silverstein, R.A. and Ekwall, K. (2005) Sin3: A flexible regulator of global gene expression and genome stability. Current Genetics, 47, 1-17. doi: 10.1007/s00294-004-0541-5
[4] Li, J., Wang, J., Nawaz, Z., Liu, J.M., Qin, J. and Wong, J. (2000) Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. Embo Journal, 19, 4342-4350. doi:10.1093/emboj/19.16.4342
[5] Gao, Z., Chiao, P., Zhang, X., Lazar, M.A., Seto, E., Young, H.A. and Ye, J. (2005) Coactivators and corepressors of NF-κB in IκBα gene promoter. Journal of Biological Chemistry, 280, 21091-21098. doi:10.1074/jbc.M500754200
[6] Riester, D., Hildmann, C. and Schwienhorst, A. (2007) Histone deacetylase inhibitors—Turning epigenic mechanisms of gene regulation into tools of therapeutic intervention in malignant and other diseases. Applied Microbiological Biotechnology, 75, 499-514. doi:10.1007/s00253-007-0912-1
[7] Pulukuri, S.M., Gorantla, B. and Rao, J.S. (2007) Inhibition of histone deacetylase activity promotes invasion of human cancer cells through activation of urokinase plasminogen activator. Journal of Biological Chemistry, 282, 35594-35603. doi: 10.1074/jbc.M705867200
[8] Cretu, A., Sha, X., Tront, J., Hoffman, B. and Liebermann, D.A. (2009) Stress sensor Gadd45 genes as therapeutic targets in cancer. Cancer Therapy, 7, 268-276.
[9] Hoffman, B. and Liebermann, D.A. (2009) Gadd45 mo- dulation of intrinsic and extrinsic stress responses in mye- loid cells. Journal of Cell Physiology, 218, 26-31. doi:10.1002/jcp.21582
[10] Hatayama, H., Iwashita, J., Kuwajima, A. and Abe, T. (2007) The short chain fatty acid, butyrate, stimulates MUC2 mucin production in the human colon cancer cell line, LS174T. Biochemical and Biophysical Research Com- munications, 356, 599-603. doi:10.1016/j.bbrc.2007.03.025
[11] Chen, Z., Clark, S., Birkeland, M., Sung, C.M., Lago, A., Liu, R., Kirkpatrick, R., Johanson, K., Winkler, J.D. and Hu, E. (2002) Induction and superinduction of growth arrest and DNA damage gene 45 (GADD45) α and β messenger RNAs by histone deacetylase inhibitors tricho- statin A (TSA) and butyrate in SW620 human colon carcinoma cells. Cancer Letters, 188, 127-140. doi:10.1016/S0304-3835(02)00322-1
[12] Zumbrun, S.D., Hoffman, B. and Liebermann, D.A. (2009) Distinct mechanisms are utilized to induce stress sensor gadd45β by different stress stimuli. Journal of Cell Biochemistry, 108, 1220-1231. doi:10.1002/jcb.22354
[13] Yoshida, M., Furumai, R., Nishiyama, M., Komatsu, Y., Nishino, N. and Horinouchi, S. (2001) Histone deacetylase as a new target for cancer chemotherapy. Cancer Chemotherapy and Pharmacology, 48, S20-S26. doi:10.1007/s002800100300
[14] Iwashita, J., Yamamoto, T., Sasaki, Y. and Abe, T. (2010) MUC5AC production is downregulated in NCI-H292 lung cancer cells cultured on type-IV collagen. Molecular Cell Biochemistry, 337, 65-75. doi: 10.1007/s11010-009-0286-z
[15] Erisman, M.D., Rothberg, P.G., Diehl, R.E., Morse, C.C., Spandorfer, J.M. and Astrin, S.M. (1985) Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Molecular and Cellular Biology, 5, 1969-1976. doi:10.1128/MCB.5.8.1969
[16] Seoane, J., Le, H.V. and Massague, J. (2002) Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. Nature, 419, 729-734. doi:10.1038/nature01119
[17] Millau, J.F., Bastien, N., Bouchard, E.F. and Drouin, R. (2009) p53 pre- and post-binding event theories revisited: stresses reveal specific and dynamic p53-binding patterns on the p21 gene promoter. Cancer Research, 69, 8463- 8471. doi: 10.1158/0008-5472.CAN-09-2036
[18] Habold, C., Poehlmann, A., Bajbouj, K., Hartig, R., Korkmaz, K.S., Roessner, A. and Schneider-Stock, R. (2008) Trichostatin A causes p53 to switch oxidative-damaged colorectal cancer cells from cell cycle arrest into apoptosis. Journal of Cellular and Molecular Medicine, 12, 607-621. doi:10.1111/j.1582-4934.2007.00136.x
[19] Liu, P.Y., Chan, J.Y., Lin, H.C., Wang, S.L., Liu, S.T., Ho, C.L., Chang, L.C. and Huang, S.M. (2008) Modulation of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 gene by Zac1 through the antagonistic regulators p53 and histone deacetylase 1 in HeLa Cells. Molecular Cancer Research, 6, 1204-1214. doi:10.1158/1541-7786.MCR-08-0123
[20] Ocker, M. and Schneider-Stock, R. (2007) Histone dea- cetylase inhibitors: signalling towards p21cip1/waf1. The International Journal of Biochemistry & Cell Biology, 39, 1367-1374. doi:10.1016/j.biocel.2007.03.001
[21] Li, H. and Wu, X. (2004) Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells. Biochemical and Biophysical Research Communications, 324, 860-867. doi:10.1016/j.bbrc.2004.09.130
[22] Schepeler, T., Mansilla, F., Christensen, L.L., Orntoft, T. F. and Andersen, C.L. (2007) Clusterin expression can be modulated by changes in TCF1-mediated Wnt signaling. Journal of Molecular Signaling, 2, 6. doi:10.1186/1750-2187-2-6
[23] Violette, S., Poulain, L., Dussaulx, E., Pepin, D., Faussat, A. M., Chambaz, J., Lacorte, J.M., Staedel, C. and Lesuffleur, T. (2002) Resistance of colon cancer cells to long- term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status. International Journal of Cancer, 98, 498-504. doi:10.1002/ijc.10146
[24] Oliner, J.D., Pietenpol, J.A., Thiagalingam, S., Gyuris, J., Kinzler, K.W. and Vogelstein, B. (1993) Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature, 362, 857-860. doi:10.1038/362857a0
[25] Kearsey, J.M., Coates, P.J., Prescott, A.R., Warbrick, E. and Hall, P.A. (1995) Gadd45 is a nuclear cell cycle re- gulated protein which interacts with p21(Cip1). Oncogene, 11, 1675-1683.
[26] Arvanitis, C. and Felsher, D.W. (2006) Conditional trans- genic models define how MYC initiates and maintains tu- morigenesis. Seminars in Cancer Biology, 16, 313-317. doi:10.1016/j.semcancer.2006.07.012

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