Trichostatin A induces mesenchymal-like morphological change and gene expression but inhibits migration and colony formation in human cancer cells

Han,Rong-Fei; Li,Kai; Yang,Zi-Shan; Chen,Zhi-Guo; Yang,Wan-Cai

doi:10.3892/mmr.2014.2594

Trichostatin A induces mesenchymal-like morphological change and gene expression but inhibits migration and colony formation in human cancer cells

Authors:
- Rong-Fei Han
- Kai Li
- Zi-Shan Yang
- Zhi-Guo Chen
- Wan-Cai Yang
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Affiliations: Department of Biochemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China, Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
Published online on: September 23, 2014 https://doi.org/10.3892/mmr.2014.2594
Pages: 3211-3216

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Abstract

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl from lysine residues in histones and other proteins, which results in gene transcriptional repression and subsequent changes in signaling events. HDACs inhibitors (HDACIs) have been used to reverse the aberrant epigenetic changes associated with cancer. However, the effects of HDACIs on epithelial-mesenchymal transition (EMT) in human cancer cells remain unclear. EMT is a fundamental process governing morphogenesis in multicellular organisms and promotes cancer invasion and metastasis. In this study, human cancer cells were treated with the HDACI trichostatin A (TSA). TSA was found to induce mesenchymal‑like morphological changes in BGC-823 human gastric cancer and MCF-7 breast cancer cells, and increase the expression levels of the mesenchymal markers Vimentin and Twist. However, the expression levels of the epithelial cell marker E-cadherin were also increased in response to TSA treatment, while cell migration was reduced by TSA. Furthermore, TSA decreased cancer cell colony formation in BGC-823 and MCF-7 cells, and led to the deregulation of β-catenin, a critical signaling molecule involved in EMT. In conclusion, the results suggested that TSA exhibits dual functions in EMT induction and inhibition in human cancer cells, but the detailed mechanisms require further investigation.

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1	Chaffer CL and Weinberg RA: A perspective on cancer cell metastasis. Science. 331:1559–1564. 2011. View Article : Google Scholar : PubMed/NCBI
2	Sahai E: Illuminating the metastatic process. Nat Rev Cancer. 7:737–749. 2007. View Article : Google Scholar : PubMed/NCBI
3	Kang Y and Massagué J: Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 118:277–279. 2004. View Article : Google Scholar : PubMed/NCBI
4	Lu J, Guo H, Treekitkarnmongkol W, et al: 14-3-3ζ cooperates with ErbB2 to promote progression of ductal carcinoma in situ progression to invasive breast cancer by inducing epithelial-mesenchymal transition. Cancer Cell. 16:195–207. 2009.
5	Mani SA, Guo W, Liao MJ, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI
6	Buchwald M, Krämer OH and Heinzel T: HDACi - targets beyond chromatin. Cancer Lett. 280:160–167. 2009. View Article : Google Scholar : PubMed/NCBI
7	Acharya MR, Sparreboom A, Venitz J and Figg WD: Rational development of histone deacetylase inhibitors as anticancer agents: a review. Mol Pharmacol. 68:917–932. 2005. View Article : Google Scholar : PubMed/NCBI
8	Yoshikawa M, Hishikawa K, Marumo T and Fujita T: Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells. J Am Soc Nephrol. 18:58–65. 2007. View Article : Google Scholar
9	Bruzzese F, Leone A, Rocco M, et al: HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT. J Cell Physiol. 226:2378–2390. 2011. View Article : Google Scholar : PubMed/NCBI
10	Kong D, Ahmad A, Bao B, et al: Histone deacetylase inhibitors induce epithelial-to-mesenchymal transition in prostate cancer cells. PloS One. 7:e450452012. View Article : Google Scholar : PubMed/NCBI
11	Bolden JE, Peart MJ and Johnstone RW: Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 5:769–784. 2006. View Article : Google Scholar : PubMed/NCBI
12	Scheel C, Eaton EN, Li SH, et al: Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 145:926–940. 2011. View Article : Google Scholar : PubMed/NCBI
13	Roth SY, Denu JM and Allis CD: Histone acetyltransferases. Annu Rev Biochem. 70:81–120. 2001. View Article : Google Scholar : PubMed/NCBI
14	Dokmanovic M, Clarke C and Marks PA: Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 5:981–989. 2007. View Article : Google Scholar : PubMed/NCBI
15	Huber MA, Kraut N and Beug H: Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 17:548–558. 2005. View Article : Google Scholar : PubMed/NCBI
16	Juan LJ, Shia WJ, Chen MH, et al: Histone deacetylases specifically down-regulate p53-dependent gene activation. J Biol Chem. 275:20436–20443. 2000. View Article : Google Scholar
17	Ashburner BP, Westerheide SD and Baldwin AS Jr: The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol Cell Biol. 21:7065–7077. 2001. View Article : Google Scholar : PubMed/NCBI
18	Winer IS, Bommer GT, Gonik N and Fearon ER: Lysine residues Lys-19 and Lys-49 of beta-catenin regulate its levels and function in T cell factor transcriptional activation and neoplastic transformation. J Biol Chem. 281:26181–26187. 2006. View Article : Google Scholar
19	Li VS, Ng SS, Boersema PJ, et al: Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell. 149:1245–1256. 2012. View Article : Google Scholar : PubMed/NCBI
20	Li Y, Zhang X, Polakiewicz RD, et al: HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization. J Biol Chem. 283:12686–12690. 2008. View Article : Google Scholar : PubMed/NCBI
21	Mak AB, Nixon AM, Kittanakom S, et al: Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress cancer cell differentiation. Cell Rep. 2:951–963. 2012.PubMed/NCBI
22	Bi X, Pohl N, Qian Z, et al: Decorin-mediated inhibition of colorectal cancer growth and migration is associated with E-cadherin in vitro and in mice. Carcinogenesis. 33:326–330. 2012. View Article : Google Scholar : PubMed/NCBI