Histone deacetylase 4 mediates SMAD family member 4 deacetylation and induces 5-fluorouracil resistance in breast cancer cells

Yu,Seong-Lan; Lee,Dong  Chul; Son,Ji  Woong; Park,Chang   Gyo; Lee,Hoi  Young; Kang,Jaeku

doi:10.3892/or.2013.2578

Histone deacetylase 4 mediates SMAD family member 4 deacetylation and induces 5-fluorouracil resistance in breast cancer cells

Authors:
- Seong-Lan Yu
- Dong Chul Lee
- Ji Woong Son
- Chang Gyo Park
- Hoi Young Lee
- Jaeku Kang
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Affiliations: Department of Pharmacology, College of Medicine, Konyang University, Daejeon 302-718, Republic of Korea, Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305‑806, Republic of Korea, Department of Internal Medicine, Konyang University Hospital, Daejeon 302-718, Republic of Korea
Published online on: July 1, 2013 https://doi.org/10.3892/or.2013.2578
Pages: 1293-1300

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Abstract

Histone deacetylases (HDACs) have been shown to play important roles in the regulation of chromatin remodeling by histone deacetylation, and their expression is induced in several types of cancer. In addition, they are known to be associated with resistance to anticancer drugs. However, the relevance of HDAC4 in chemoresistance remains unclear. Therefore, we investigated the interaction between HDAC4 expression and chemoresistance in breast cancer cells. We found that increased HDAC4 expression in MDA-MB-231 cells was associated with resistance to the anticancer drug 5-fluorouracil (5-FU). To verify these results, a cell line stably overexpressing HDAC4 was generated using MCF-7 cells (HDAC4OE). This cell line displayed increased 5-FU resistance, and HDAC4 knockdown in HDAC4OE cells restored 5-FU sensitivity. Consequently, we concluded that HDAC4 is a critical gene associated with 5‑FU chemoresistance. Further investigation using a microarray approach revealed that 355 genes were differentially expressed following HDAC4 overexpression. Based on functional annotation of the array results, HDAC4 overexpression was found to downregulate genes related to the transforming growth factor (TGF) β signaling pathway, including SMAD4, SMAD6, bone morphogenetic protein 6, inhibitor of DNA binding 1 and TGFβ2. We also found that HDAC4 expression regulates SMAD4 expression by inducing deacetylation of histone H3 in the SMAD4 promoter region. In addition, SMAD4 knockdown in MCF‑7 cells increased 5-FU resistance. In summary, our data suggest that HDAC4‑mediated deacetylation of the SMAD4 promoter may lead to 5-FU resistance in breast cancer cells.

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1	Jones PA and Baylin SB: The epigenomics of cancer. Cell. 128:683–692. 2007. View Article : Google Scholar : PubMed/NCBI
2	Ellis L, Atadja PW and Johnstone RW: Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther. 8:1409–1420. 2009. View Article : Google Scholar : PubMed/NCBI
3	Sandoval J and Esteller M: Cancer epigenomics: beyond genomics. Curr Opin Genet Dev. 22:50–55. 2012. View Article : Google Scholar : PubMed/NCBI
4	Nakagawa M, Oda Y, Eguchi T, et al: Expression profile of class I histone deacetylases in human cancer tissues. Oncol Rep. 18:769–774. 2007.PubMed/NCBI
5	Khan O and La Thangue NB: HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol. 90:85–94. 2012. View Article : Google Scholar : PubMed/NCBI
6	Dell’Aversana C, Lepore I and Altucci L: HDAC modulation and cell death in the clinic. Exp Cell Res. 318:1229–1244. 2012.PubMed/NCBI
7	Song B, Wang Y, Xi Y, et al: Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells. Oncogene. 28:4065–4074. 2009. View Article : Google Scholar : PubMed/NCBI
8	Crea F, Nobili S, Paolicchi E, et al: Epigenetics and chemoresistance in colorectal cancer: an opportunity for treatment tailoring and novel therapeutic strategies. Drug Resist Updat. 14:280–296. 2011. View Article : Google Scholar : PubMed/NCBI
9	Geng H, Harvey CT, Pittsenbarger J, et al: HDAC4 protein regulates HIF1α protein lysine acetylation and cancer cell response to hypoxia. J Biol Chem. 286:38095–38102. 2011.
10	Tinari N, De Tursi M, Grassadonia A, et al: An epigenetic approach to pancreatic cancer treatment: the prospective role of histone deacetylase inhibitors. Curr Cancer Drug Targets. 12:439–452. 2012. View Article : Google Scholar : PubMed/NCBI
11	Kim MG, Pak JH, Choi WH, Park JY, Nam JH and Kim JH: The relationship between cisplatin resistance and histone deacetylase isoform overexpression in epithelial ovarian cancer cell lines. J Gynecol Oncol. 23:182–189. 2012. View Article : Google Scholar : PubMed/NCBI
12	Park SY, Jun JA, Jeong KJ, et al: Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer. Oncol Rep. 25:1677–1681. 2011.PubMed/NCBI
13	Stronach EA, Alfraidi A, Rama N, et al: HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer. Cancer Res. 71:4412–4422. 2011. View Article : Google Scholar : PubMed/NCBI
14	Papageorgis P, Cheng K, Ozturk S, et al: Smad4 inactivation promotes malignancy and drug resistance of colon cancer. Cancer Res. 71:998–1008. 2011. View Article : Google Scholar : PubMed/NCBI
15	Takagi Y, Kohmura H, Futamura M, et al: Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology. 111:1369–1372. 1996. View Article : Google Scholar : PubMed/NCBI
16	Wang LH, Kim SH, Lee JH, et al: Inactivation of SMAD4 tumor suppressor gene during gastric carcinoma progression. Clin Cancer Res. 13:102–110. 2007. View Article : Google Scholar : PubMed/NCBI
17	Hahn SA, Schutte M, Hoque AT, et al: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 271:350–353. 1996. View Article : Google Scholar : PubMed/NCBI
18	Schutte M, Hruban RH, Hedrick L, et al: DPC4 gene in various tumor types. Cancer Res. 56:2527–2530. 1996.PubMed/NCBI
19	Nagatake M, Takagi Y, Osada H, et al: Somatic in vivo alterations of the DPC4 gene at 18q21 in human lung cancers. Cancer Res. 56:2718–2720. 1996.PubMed/NCBI
20	Aitchison AA, Veerakumarasivam A, Vias M, et al: Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer. Prostate. 68:661–674. 2008. View Article : Google Scholar : PubMed/NCBI
21	Han S, Lu J, Zhang Y, et al: Recruitment of histone deacetylase 4 by transcription factors represses interleukin-5 transcription. Biochemical J. 400:439–448. 2006. View Article : Google Scholar : PubMed/NCBI
22	Wang X, Feng Y, Xu L, et al: YY1 restrained cell senescence through repressing the transcription of p16. Biochim Biophys Acta. 1783:1876–1883. 2008. View Article : Google Scholar : PubMed/NCBI
23	Ren G, Zhang G, Dong Z, et al: Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers. Int J Biochem Cell Biol. 41:1094–1101. 2009. View Article : Google Scholar : PubMed/NCBI
24	Reddy SD, Pakala SB, Molli PR, et al: Metastasis-associated protein 1/histone deacetylase 4-nucleosome remodeling and deacetylase complex regulates phosphatase and tensin homolog gene expression and function. J Biol Chem. 287:27843–27850. 2012. View Article : Google Scholar
25	Fraga MF, Ballestar E, Villar-Garea A, et al: Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 37:391–400. 2005. View Article : Google Scholar : PubMed/NCBI
26	Elsheikh SE, Green AR, Rakha EA, et al: Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res. 69:3802–3809. 2009. View Article : Google Scholar : PubMed/NCBI
27	Seligson DB, Horvath S, Shi T, et al: Global histone modification patterns predict risk of prostate cancer recurrence. Nature. 435:1262–1266. 2005. View Article : Google Scholar : PubMed/NCBI
28	Barlési F, Giaccone G, Gallegos-Ruiz MI, et al: Global histone modifications predict prognosis of resected non small-cell lung cancer. J Clin Oncol. 25:4358–4364. 2007.PubMed/NCBI
29	Uluer ET, Aydemir I, Inan S, Ozbilgin K and Vatansever HS: Effects of 5-fluorouracil and gemcitabine on a breast cancer cell line (MCF-7) via the JAK/STAT pathway. Acta Histochem. 114:641–646. 2012. View Article : Google Scholar : PubMed/NCBI
30	Zheng G, Xiong Y, Yi S, et al: 14-3-3σ regulation by p53 mediates a chemotherapy response to 5-fluorouracil in MCF-7 breast cancer cells via Akt inactivation. FEBS Lett. 586:163–168. 2012.
31	Shi Q, Zhong YS, Yao LQ, et al: Down-regulation of Smad4 enhances proliferation and invasion of colorectal carcinoma HCT116 cells and up-regulates Id2. Mol Med Rep. 5:89–95. 2012.PubMed/NCBI
32	Kim JY, Park DY, Kim GH, et al: Smad4 expression in gastric adenoma and adenocarcinoma: frequent loss of expression in diffuse type of gastric adenocarcinoma. Histol Histopathol. 20:543–549. 2005.PubMed/NCBI
33	Stuelten CH, Buck MB, Dippon J, Roberts AB, Fritz P and Knabbe C: Smad4-expression is decreased in breast cancer tissues: a retrospective study. BMC cancer. 6:252006. View Article : Google Scholar : PubMed/NCBI
34	de Kruijf EM, Dekker TJ, Hawinkels LJ, et al: The prognostic role of TGF-β signaling pathway in breast cancer patients. Ann Oncol. 24:384–390. 2013.
35	He SM, Zhao ZW, Wang Y, et al: Reduced expression of SMAD4 in gliomas correlates with progression and survival of patients. J Exp Clin Cancer Res. 30:702011. View Article : Google Scholar : PubMed/NCBI
36	Li Q, Wu L, Oelschlager DK, et al: Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-alpha-positive breast cancer cells. J Biol Chem. 280:27022–27028. 2005. View Article : Google Scholar : PubMed/NCBI
37	Wilson AJ, Byun DS, Nasser S, et al: HDAC4 promotes growth of colon cancer cells via repression of p21. Mol Biol Cell. 19:4062–4075. 2008. View Article : Google Scholar : PubMed/NCBI
38	Mottet D, Pirotte S, Lamour V, et al: HDAC4 represses p21 (WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism. Oncogene. 28:243–256. 2009. View Article : Google Scholar : PubMed/NCBI