Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

Abstract

Histone deacetylases (HDACs) are frequently overexpressed in broad range of cancer types, where they alter cellular epigenetic programming to promote cell proliferation and survival. However, the mechanism by which HDACs become overexpressed in human cancers remains somewhat of a mystery. In this study, we investigated the expression and functional significance of miR-449a in prostate cancer cells. Using real-time PCR, we found that miR-449a is downregulated in prostate cancer tissues relative to patient-matched control tissue. Introduction of miR-449a into PC-3 prostate cancer cells resulted in cell-cycle arrest, apoptosis and a senescent-like phenotype. In silico analysis of 3′-UTR regions identified a number of genes involved in cell-cycle regulation as putative targets of miR-449a. Using a luciferase 3′-UTR reporter system, we established that HDAC-1 (histone deacetylase 1), a gene that is frequently overexpressed in many types of cancer, is a direct target of miR-449a. Further, our data indicate that miR-449a regulates cell growth and viability in part by repressing the expression of HDAC-1 in prostate cancer cells. Our findings provide new insight into the function of miRNA in regulating HDAC expression in normal versus cancerous tissue.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning MJ et al. (2007). MicroRNA expression profiling of human breast cancer identifies new markers of tumour subtype. Genome Biol 8: R214.

    Article  PubMed Central  Google Scholar 

  • Chen JS, Faller DV . (2005). Histone deacetylase inhibition-mediated post-translational elevation of p27KIP1 protein levels is required for G1 arrest in fibroblasts. J Cell Physiol 202: 87–99.

    Article  CAS  Google Scholar 

  • Chen Y, Stallings RL . (2007). Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis, differentiation, and apoptosis. Cancer Res 67: 976–983.

    Article  CAS  Google Scholar 

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C et al. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92: 9363–9367.

    Article  CAS  PubMed Central  Google Scholar 

  • Duan H, Heckman CA, Boxer LM . (2005). Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol 25: 1608–1619.

    Article  CAS  PubMed Central  Google Scholar 

  • Fulci V, Chiaretti S, Goldoni M, Azzalin G, Carucci N, Tavolaro S et al. (2007). Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood 109: 4944–4951.

    Article  CAS  Google Scholar 

  • Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG et al. (2008). Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid (SAHA)) in patients with advanced leukemias and myelodysplastic syndromes. Blood 111: 1060–1066.

    Article  CAS  Google Scholar 

  • Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C et al. (2007). Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res 67: 2456–2468.

    Article  CAS  Google Scholar 

  • Glaser KB, Li J, Staver MJ, Wei RQ, Albert DH, Davidsen SK . (2003). Role of class I and class II histone deacetylases in carcinoma cells using siRNA. Biochem Biophys Res Commun 310: 529–536.

    Article  CAS  Google Scholar 

  • Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP . (2007). MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27: 91–105.

    Article  CAS  PubMed Central  Google Scholar 

  • Halkidou K, Gaughan L, Cook S, Leung HY, Neal DE, Robson CN . (2004). Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate 59: 177–189.

    Article  CAS  Google Scholar 

  • He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y et al. (2007). A microRNA component of the p53 tumour suppressor network. Nature 447: 1130–1134.

    Article  CAS  PubMed Central  Google Scholar 

  • Hitomi T, Matsuzaki Y, Yokota T, Takaoka Y, Sakai T . (2003). p15(INK4b) in HDAC inhibitor-induced growth arrest. FEBS Lett 554: 347–350.

    Article  CAS  Google Scholar 

  • Iacomino G, Medici MC, Russo GL . (2008). Valproic acid sensitizes K562 erythroleukemia cells to TRAIL/Apo2L-induced apoptosis. Anticancer Res 28: 855–864.

    CAS  PubMed  Google Scholar 

  • Inoue S, Mai A, Dyer MJ, Cohen GM . (2006). Inhibition of histone deacetylase class I but not class II is critical for the sensitization of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 66: 6785–6792.

    Article  CAS  Google Scholar 

  • Jiang J, Lee EJ, Gusev Y, Schmittgen TD . (2005). Real-time expression profiling of microRNA precursors in human cancer cell lines. Nucleic Acids Res 33: 5394–5403.

    Article  CAS  PubMed Central  Google Scholar 

  • Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM et al. (2002). The human genome browser at UCSC. Genome Res 12: 996–1006.

    Article  CAS  PubMed Central  Google Scholar 

  • Kim HR, Kim EJ, Yang SH, Jeong ET, Park C, Lee JH et al. (2006). Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway? Exp Mol Med 38: 616–624.

    Article  CAS  Google Scholar 

  • Kim JH, Choi YK, Kwon HJ, Yang HK, Choi JH, Kim DY . (2004). Downregulation of gelsolin and retinoic acid receptor beta expression in gastric cancer tissues through histone deacetylase 1. J Gastroenterol Hepatol 19: 218–224.

    Article  CAS  Google Scholar 

  • Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW et al. (2001). Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7: 437–443.

    Article  PubMed Central  Google Scholar 

  • Kummar S, Gutierrez M, Gardner ER, Donovan E, Hwang K, Chung EJ et al. (2007). Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin Cancer Res 13: 5411–5417.

    Article  CAS  Google Scholar 

  • Kurz DJ, Decary S, Hong Y, Erusalimsky JD . (2000). Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 113 (Part 20): 3613–3622.

    CAS  PubMed  Google Scholar 

  • Lagger G, O'Carroll D, Rembold M, Khier H, Tischler J, Weitzer G et al. (2002). Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 21: 2672–2681.

    Article  CAS  PubMed Central  Google Scholar 

  • Lewis BP, Burge CB, Bartel DP . (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.

    Article  CAS  PubMed Central  Google Scholar 

  • Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB . (2003). Prediction of mammalian microRNA targets. Cell 115: 787–798.

    CAS  PubMed  Google Scholar 

  • Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. (2005). MicroRNA expression profiles classify human cancers. Nature 435: 834–838.

    Article  CAS  PubMed Central  Google Scholar 

  • Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R . (2007). FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12: 1247–1252.

    Article  CAS  PubMed Central  Google Scholar 

  • Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK . (2001). Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1: 194–202.

    Article  CAS  PubMed Central  Google Scholar 

  • Mattie MD, Benz CC, Bowers J, Sensinger K, Wong L, Scott GK et al. (2006). Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer 5: 24.

    Article  PubMed Central  Google Scholar 

  • Mehnert JM, Kelly WK . (2007). Histone deacetylase inhibitors: biology and mechanism of action. Cancer J 13: 23–29.

    Article  CAS  Google Scholar 

  • Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T . (2007). MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133: 647–658.

    Article  CAS  PubMed Central  Google Scholar 

  • Ozen M, Creighton CJ, Ozdemir M, Ittmann M . (2008). Widespread deregulation of microRNA expression in human prostate cancer. Oncogene 27: 1788–1793.

    Article  CAS  Google Scholar 

  • Pan Y, Lui WO, Nupponen N, Larsson C, Isola J, Visakorpi T et al. (2001). 5q11, 8p11, and 10q22 are recurrent chromosomal breakpoints in prostate cancer cell lines. Genes Chromosomes Cancer 30: 187–195.

    Article  CAS  Google Scholar 

  • Patra SK, Patra A, Dahiya R . (2001). Histone deacetylase and DNA methyltransferase in human prostate cancer. Biochem Biophys Res Commun 287: 705–713.

    Article  CAS  Google Scholar 

  • Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R . (2008). MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA 105: 1608–1613.

    Article  CAS  Google Scholar 

  • Place RF, Noonan EJ, Giardina C . (2005). HDACs and the senescent phenotype of WI-38 cells. BMC Cell Biol 6: 37.

    Article  PubMed Central  Google Scholar 

  • Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T . (2007). MicroRNA expression profiling in prostate cancer. Cancer Res 67: 6130–6135.

    Article  CAS  Google Scholar 

  • Pressman S, Bei Y, Carthew R . (2007). Snapshot: posttranscriptional gene silencing. Cell 130: 570.

    Article  Google Scholar 

  • Qian DZ, Wei YF, Wang X, Kato Y, Cheng L, Pili R . (2007). Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models. Prostate 67: 1182–1193.

    Article  CAS  Google Scholar 

  • Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N et al. (2007). Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 26: 731–743.

    Article  CAS  PubMed Central  Google Scholar 

  • Senese S, Zaragoza K, Minardi S, Muradore I, Ronzoni S, Passafaro A et al. (2007). Role for histone deacetylase 1 in human tumor cell proliferation. Mol Cell Biol 27: 4784–4795.

    Article  CAS  PubMed Central  Google Scholar 

  • Shabbeer S, Kortenhorst MS, Kachhap S, Galloway N, Rodriguez R, Carducci MA . (2007). Multiple molecular pathways explain the anti-proliferative effect of valproic acid on prostate cancer cells in vitro and in vivo. Prostate 67: 1099–1110.

    Article  CAS  Google Scholar 

  • Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA et al. (2007). Let-7 expression defines two differentiation stages of cancer. Proc Natl Acad Sci USA 104: 11400–11405.

    Article  CAS  PubMed Central  Google Scholar 

  • Spurling CC, Godman CA, Noonan EJ, Rasmussen TP, Rosenberg DW, Giardina C . (2008). HDAC3 overexpression and colon cancer cell proliferation and differentiation. Mol Carcinog 47: 137–147.

    Article  CAS  Google Scholar 

  • Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A et al. (2007). Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 6: 1586–1593.

    Article  CAS  PubMed Central  Google Scholar 

  • Tazawa H, Tsuchiya N, Izumiya M, Nakagama H . (2007). Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci USA 104: 15472–15477.

    Article  CAS  PubMed Central  Google Scholar 

  • Tong AW, Nemunaitis J . (2008). Modulation of miRNA activity in human cancer: a new paradigm for cancer gene therapy? Cancer Gene Ther 15: 341–355.

    Article  CAS  Google Scholar 

  • Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F et al. (2006). A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103: 2257–2261.

    Article  CAS  PubMed Central  Google Scholar 

  • Wagner M, Brosch G, Zwerschke W, Seto E, Loidl P, Jansen-Durr P . (2001). Histone deacetylases in replicative senescence: evidence for a senescence-specific form of HDAC-2. FEBS Lett 499: 101–106.

    Article  CAS  Google Scholar 

  • Wedel SA, Sparatore A, Del Soldato P, Al-Batran SE, Atmaca A, Juengel E et al. (2008). New histone deacetylase inhibitors as potential therapeutic tools for advanced prostate carcinoma. J Cell Mol Med 12: 2457–2466.

    Article  CAS  PubMed Central  Google Scholar 

  • Weichert W, Roske A, Gekeler V, Beckers T, Stephan C, Jung K et al. (2008a). 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 98: 604–610.

    Article  CAS  PubMed Central  Google Scholar 

  • Weichert W, Roske A, Niesporek S, Noske A, Buckendahl AC, Dietel M et al. (2008b). 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 14: 1669–1677.

    Article  CAS  Google Scholar 

  • Wiklund F, Gillanders EM, Albertus JA, Bergh A, Damber JE, Emanuelsson M et al. (2003). Genome-wide scan of Swedish families with hereditary prostate cancer: suggestive evidence of linkage at 5q11.2 and 19p13.3. Prostate 57: 290–297.

    Article  CAS  Google Scholar 

  • Wilson AJ, Byun DS, Popova N, Murray LB, L'Italien K, Sowa Y et al. (2006). Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J Biol Chem 281: 13548–13558.

    Article  CAS  Google Scholar 

  • Xu WS, Parmigiani RB, Marks PA . (2007). Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26: 5541–5552.

    Article  CAS  Google Scholar 

  • Yoshikawa M, Hishikawa K, Marumo T, Fujita T . (2007). 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.

    Article  CAS  Google Scholar 

  • Zhang Z, Yamashita H, Toyama T, Sugiura H, Ando Y, Mita K et al. (2005). Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast*. Breast Cancer Res Treat 94: 11–16.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R Erickson for his critical reading and discussion of the paper. This work was supported by the Veterans Affairs Research Enhancement Award Program (REAP), VA Merit Review grant and the National Institutes of Health grants RO1CA101844, RO1CA111470s and T32DK007790 (PI: Rajvir Dahiya).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to E J Noonan or R Dahiya.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Noonan, E., Place, R., Pookot, D. et al. miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene 28, 1714–1724 (2009). https://doi.org/10.1038/onc.2009.19

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.19

Keywords

This article is cited by

Search

Quick links