Phenotypic impact of deregulated expression of class I histone deacetylases in urothelial cell carcinoma of the bladder
Susana Junqueira-Neto
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Search for more papers by this authorFilipa Q. Vieira
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
School of Allied Health Sciences ESTSP, Polytechnic of Porto, Porto, Portugal
Search for more papers by this authorDiana Montezuma
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Department of Pathology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorNatália R. Costa
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Search for more papers by this authorLuís Antunes
Department of Epidemiology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorTiago Baptista
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Search for more papers by this authorAna Isabel Oliveira
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Search for more papers by this authorInês Graça
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
School of Allied Health Sciences ESTSP, Polytechnic of Porto, Porto, Portugal
Search for more papers by this authorÂngelo Rodrigues
Department of Pathology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorJosé S. Magalhães
Department of Urology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorJorge Oliveira
Department of Urology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorRui Henrique
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Department of Pathology, Portuguese Oncology Institute, Porto, Portugal
Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
Search for more papers by this authorCorresponding Author
Carmen Jerónimo
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
Correspondence to: Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal.Search for more papers by this authorSusana Junqueira-Neto
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Search for more papers by this authorFilipa Q. Vieira
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
School of Allied Health Sciences ESTSP, Polytechnic of Porto, Porto, Portugal
Search for more papers by this authorDiana Montezuma
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Department of Pathology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorNatália R. Costa
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Search for more papers by this authorLuís Antunes
Department of Epidemiology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorTiago Baptista
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Search for more papers by this authorAna Isabel Oliveira
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Search for more papers by this authorInês Graça
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
School of Allied Health Sciences ESTSP, Polytechnic of Porto, Porto, Portugal
Search for more papers by this authorÂngelo Rodrigues
Department of Pathology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorJosé S. Magalhães
Department of Urology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorJorge Oliveira
Department of Urology, Portuguese Oncology Institute, Porto, Portugal
Search for more papers by this authorRui Henrique
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Department of Pathology, Portuguese Oncology Institute, Porto, Portugal
Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
Search for more papers by this authorCorresponding Author
Carmen Jerónimo
Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, Portugal
Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
Correspondence to: Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal.Search for more papers by this authorABSTRACT
Deregulated expression of histone deacetylases (HDACs) has been implicated in tumorigenesis. Herein, we investigated class I HDACs expression in bladder urothelial cell carcinoma (BUCC), its prognostic value and biological significance. Significantly increased transcript levels of all HDACs were found in BUCC compared to 20 normal mucosas, and these were higher in lower grade and stage tumors. Increased HDAC3 levels were associated with improved patient survival. SiRNA experiments showed decrease cell viability and motility, and increased apoptosis. We concluded that class I HDACs play an important role in bladder carcinogenesis through deregulation of proliferation, migration and apoptosis, constituting putative therapeutic targets. © 2013 Wiley Periodicals, Inc.
Supporting Information
Additional supporting information may be found in the online version of this article at the publisher's web-site.
| Filename | Description |
|---|---|
| mc22117-sup-0001-SupFig-S1.tif483.8 KB | Figure S1. Transcript levels of HDAC1, HDAC2, HDAC3, and HDAC8 in bladder urothelial cell carcinoma cell lines (5637, J82, T24, and TCCSUP). |
| mc22117-sup-0002-SupFig-S2.tif142.5 KB | Figure S2. Protein levels of HDAC1, HDAC2, HDAC3, and HDAC8 in Scramble, si-HDAC1, si-HDAC2, si-HDAC3, and si-HDAC8 cells. Results were normalized to the data obtained with the Scramble and only the statistically significant results are shown (* represent statistically significant differences of si-HDACs, comparing to scramble: *P < 0.05; **P ≤ 0.01; ***P ≤ 0.001). |
| mc22117-sup-0003-SupFig-S3.tif81.4 KB | Figure S3. Protein gel blot analysis for p21 in 5637 cell line silenced for each Class I HDAC. p21 expression levels were corrected to the constitutive protein, β-actin. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893–2917. Epub 2011/02/26.
- 2 Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90. Epub 2011/02/08.
- 3 Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. Lancet 2009; 374: 239–249. Epub 2009/06/13.
- 4 Lee R, Droller MJ. The natural history of bladder cancer. Implications for therapy. Urol Clin North Am 2000; 27: 1–13, vii. Epub 2000/03/04.
- 5 Mitra AP, Cote RJ. Molecular pathogenesis and diagnostics of bladder cancer. Annu Rev Pathol 2009; 4: 251–285. Epub 2008/10/09.
- 6 Rodrigues A, Henrique R, Jerónimo C. Bladder cancer pathology (ChapterKey 306590). In: M Schwab, editor. Encyclopedia of cancer. Heidelberg, Germany: Springer; 2012.
- 7 Falke J, Witjes JA. Contemporary management of low-risk bladder cancer. Nat Rev Urol 2011; 8: 42–49. Epub 2011/01/14.
- 8 Spruck CH III, Ohneseit PF, Gonzalez-Zulueta M, et al. Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 1994; 54: 784–788. Epub 1994/02/01.
- 9 Oliveira AI, Jeronimo C, Henrique R. Moving forward in bladder cancer detection and diagnosis: The role of epigenetic biomarkers. Expert Rev Mol Diagn 2012; 12: 871–878. Epub 2012/12/20.
- 10 Bakkar AA, Wallerand H, Radvanyi F, et al. FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res 2003; 63: 8108–8112. Epub 2003/12/18.
- 11 Sidransky D, Von Eschenbach A, Tsai YC, et al. Identification of p53 gene mutations in bladder cancers and urine samples. Science 1991; 252: 706–709. Epub 1991/05/03.
- 12 Hernandez S, Lopez-Knowles E, Lloreta J, et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol 2006; 24: 3664–3671. Epub 2006/08/01.
- 13 Catto JW, Miah S, Owen HC, et al. Distinct microRNA alterations characterize high- and low-grade bladder cancer. Cancer Res 2009; 69: 8472–8481. Epub 2009/10/22.
- 14 Yates DR, Rehman I, Abbod MF, et al. Promoter hypermethylation identifies progression risk in bladder cancer. Clin Cancer Res 2007; 13: 2046–2053. Epub 2007/04/04.
- 15 Di Marcotullio L, Canettieri G, Infante P, Greco A, Gulino A. Protected from the inside: Endogenous histone deacetylase inhibitors and the road to cancer. Biochim Biophys Acta 2011; 1815: 241–252. Epub 2011/02/01.
- 16 Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem 2007; 76: 75–100. Epub 2007/03/17.
- 17 de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem J 2003; 370: 737–749. Epub 2002/11/14.
- 18 Ropero S, Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 2007; 1: 19–25. Epub 2007/06/01.
- 19 Reichert N, Choukrallah MA, Matthias P. Multiple roles of class I HDACs in proliferation, differentiation, and development. Cell Mol Life Sci 2012; 69: 2173–2187. Epub 2012/01/31.
- 20 Delcuve GP, Khan DH, Davie JR. Roles of histone deacetylases in epigenetic regulation: Emerging paradigms from studies with inhibitors. Clin Epigenet 2012; 4: 5. Epub 2012/03/15.
- 21 Weichert W, Roske A, Gekeler V, et al. Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br J Cancer 2008; 98: 604–610. Epub 2008/01/24.
- 22 Weichert W, Roske A, Niesporek S, et al. Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: Specific role of class I histone deacetylases in vitro and in vivo. Clin Cancer Res 2008; 14: 1669–1677. Epub 2008/03/19.
- 23 Weichert W, Roske A, Gekeler V, et al. Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: A retrospective analysis. Lancet Oncol 2008; 9: 139–148. Epub 2008/01/22.
- 24 Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene 2007; 26: 5420–5432. Epub 2007/08/19.
- 25 Marks P, Rifkind RA, Richon VM, et al. Histone deacetylases and cancer: Causes and therapies. Nat Rev Cancer 2001; 1: 194–202. Epub 2002/03/21.
- 26 Huang BH, Laban M, Leung CH, et al. Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ 2005; 12: 395–404. Epub 2005/01/25.
- 27 Glaser KB, Li J, Staver MJ, et al. Role of class I and class II histone deacetylases in carcinoma cells using siRNA. Biochem Biophys Res Commun 2003; 310: 529–536. Epub 2003/10/03.
- 28 Senese S, Zaragoza K, Minardi S, et al. Role for histone deacetylase 1 in human tumor cell proliferation. Mol Cell Biol 2007; 27: 4784–4795. Epub 2007/05/02.
- 29 Harms KL, Chen X. Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity. Cancer Res 2007; 67: 3145–3152. Epub 2007/04/06.
- 30 Witt O, Deubzer HE, Milde T, Oehme I. HDAC family: What are the cancer relevant targets? Cancer Lett 2009; 277: 8–21. Epub 2008/10/01.
- 31 Weichert W. HDAC expression and clinical prognosis in human malignancies. Cancer Lett 2009; 280: 168–176. Epub 2008/12/24.
- 32 Ozawa A, Tanji N, Kikugawa T, et al. Inhibition of bladder tumour growth by histone deacetylase inhibitor. BJU Int 2010; 105: 1181–1186. Epub 2009/08/18.
- 33 Netto GJ. Molecular biomarkers in urothelial carcinoma of the bladder: Are we there yet? Nat Rev Urol 2012; 9: 41–51. Epub 2011/12/14.
- 34 Zhang Z, Yamashita H, Toyama T, et al. Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast*. Breast Cancer Res Treat 2005; 94: 11–16. Epub 2005/09/21.
- 35 Van Damme M, Crompot E, Meuleman N, et al. HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance. Epigenetics 2012; 7: 1403–1412. Epub 2012/10/31.
- 36 Hassler MR, Egger G. Epigenomics of cancer—Emerging new concepts. Biochimie 2012; 94: 2219–2230.
- 37 Jung KH, Noh JH, Kim JK, et al. HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins. J Cell Biochem 2012; 113: 2167–2177. Epub 2012/04/12.
- 38 Lagger G, O'Carroll D, Rembold M, et al. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 2002; 21: 2672–2681. Epub 2002/05/29.
- 39 Yamaguchi T, Cubizolles F, Zhang Y, et al. Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev 2010; 24: 455–469. Epub 2010/03/03.
- 40 Lin KT, Yeh SH, Chen DS, Chen PJ, Jou YS. Epigenetic activation of alpha4, beta2 and beta6 integrins involved in cell migration in trichostatin A-treated Hep3B cells. J Biomed Sci 2005; 12: 803–813. Epub 2005/09/01.
- 41 Hayashi A, Horiuchi A, Kikuchi N, et al. Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin. Int J Cancer 2010; 127: 1332–1346. Epub 2010/01/06.
- 42 Zupkovitz G, Tischler J, Posch M, et al. Negative and positive regulation of gene expression by mouse histone deacetylase 1. Mol Cell Biol 2006; 26: 7913–7928. Epub 2006/08/31.
- 43 Dovey OM, Foster CT, Cowley SM. Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation. Proc Natl Acad Sci USA 2010; 107: 8242–8247. Epub 2010/04/21.
- 44 Jurkin J, Zupkovitz G, Lagger S, et al. Distinct and redundant functions of histone deacetylases HDAC1 and HDAC2 in proliferation and tumorigenesis. Cell Cycle 2011; 10: 406–412. Epub 2011/01/29.
