Abstract
Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), when compared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matched normal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005, 95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- miRNA:
-
microRNA
- ChIP:
-
chromatin immunoprecipitation
- 5-Aza-CdR:
-
5-Aza-2′-deoxycytidine
- IP:
-
immunoprecipitation
- FCS:
-
fetal calf serum
- CSFCS:
-
charcoal-stripped fetal calf Serum
- DHT:
-
dihydrotestosterone
- PSA:
-
prostate specific antigen
- AR:
-
androgen receptor
- BRFS:
-
biochemical relapse free survival.
References
Jones PA, Baylin SB . The epigenomics of cancer. Cell 2007; 128: 683–692.
Cooper CS, Foster CS . Concepts of epigenetics in prostate cancer development. Br J Cancer 2009; 100: 240–245.
Carthew RW, Sontheimer EJ . Origins and mechanisms of miRNAs and siRNAs. Cell 2009; 136: 642–655.
Cho WC . OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer 2007; 6: 60.
Ozen M, Creighton CJ, Ozdemir M, Ittmann M . Widespread deregulation of microRNA expression in human prostate cancer. Onco 2008; 27: 1788–1793.
Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, Zepeniuk M et al. MicroRNAs accurately identify cancer tissue origin. Nat Biotech 2008; 26: 462–469.
Hulf T, Sibbritt T, Wiklund ED, Bert S, Strbenac D, Statham AL et al. Discovery pipeline for epigenetically deregulated miRNAs in cancer: integration of primary miRNA transcription. BMC Genomics 2011; 12: 54.
Wu H, Zhu S, Mo YY . Suppression of cell growth and invasion by miR-205 in breast cancer. Cell Res 2009; 19: 439–448.
Iorio MV, Casalini P, Piovan C, Di Leva G, Merlo A, Triulzi T et al. microRNA-205 Regulates HER3 in human breast cancer. Cancer Res 2009; 69: 2195–2200.
Sempere LF, Christensen M, Silahtaroglu A, Bak M, Heath CV, Schwartz G et al. Altered microrna expression confined to specific epithelial cell subpopulations in breast cancer. Cancer Res 2007; 67: 11612–11620.
Gandellini P, Folini M, Longoni N, Pennati M, Binda M, Colecchia M et al. miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res 2009; 69: 2287–2295.
Neely LA, Rieger-Christ KM, Neto BS, Eroshkin A, Garver J, Patel S et al. A microRNA expression ratio defining the invasive phenotype in bladder tumors. Urol Oncol 2010; 28: 39–48.
Childs G, Fazzari M, Kung G, Kawachi N, Brandwein-Gensler M, McLemore M et al. Low-level expression of microRNAs let-7d and miR-205 are prognostic markers of head and neck squamous cell carcinoma. Am J Pathol 2009; 174: 736–745.
Feber A, Xi L, Luketich JD, Pennathur A, Landreneau RJ, Wu M et al. MicroRNA expression profiles of esophageal cancer. J Thoracic Cardiovasc Surg 2008; 135: 255–260; discussion 60.
Chung TK, Cheung TH, Huen NY, Wong KW, Lo KW, Yim SF et al. Dysregulated microRNAs and their predicted targets associated with endometrioid endometrial adenocarcinoma in Hong Kong women. Int J Cancer 2009; 124: 1358–1365.
Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P et al. MicroRNA signatures in human ovarian cancer. Cancer Res 2007; 67: 8699–8707.
Lebanony D, Benjamin H, Gilad S, Ezagouri M, Dov A, Ashkenazi K et al. Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. J Clin Oncol 2009; 27: 2030–2037.
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer cell 2006; 9: 189–198.
Markou A, Tsaroucha EG, Kaklamanis L, Fotinou M, Georgoulias V, Lianidou ES . Prognostic value of mature microRNA-21 and microRNA-205 overexpression in non-small cell lung cancer by quantitative real-time RT-PCR. Clin Chem 2008; 54: 1696–1704.
Fletcher AM, Heaford AC, Trask DK . Detection of metastatic head and neck squamous cell carcinoma using the relative expression of tissue-specific mir-205. Trans Oncol 2008; 1: 202–208.
Yu J, Ryan DG, Getsios S, Oliveira-Fernandes M, Fatima A, Lavker RM . MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia. Proc Natl Acad Sci USA 2008; 105: 19300–19305.
Tran N, McLean T, Zhang X, Zhao CJ, Thomson JM, O′Brien C et al. MicroRNA expression profiles in head and neck cancer cell lines. Biochem Biophys Res Comm 2007; 358: 12–17.
Gottardo F, Liu CG, Ferracin M, Calin GA, Fassan M, Bassi P et al. Micro-RNA profiling in kidney and bladder cancers. Urol Oncol 2007; 25: 387–392.
Ryan DG, Oliveira-Fernandes M, Lavker RM . MicroRNAs of the mammalian eye display distinct and overlapping tissue specificity. Mol Vis 2006; 12: 1175–1184.
Dijckmeester WA, Wijnhoven BP, Watson DI, Leong MP, Michael MZ, Mayne GC et al. MicroRNA-143 and −205 expression in neosquamous esophageal epithelium following Argon plasma ablation of Barrett′s esophagus. J Gastrointest Surg 2009; 13: 846–853.
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008; 10: 593–601.
Chi SW, Zang JB, Mele A, Darnell RB . Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 2009; 460: 479–486.
Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP . The impact of microRNAs on protein output. Nature 2008; 455: 64–71.
Majid S, Dar AA, Saini S, Yamamura S, Hirata H, Tanaka Y et al. MicroRNA-205-directed transcriptional activation of tumor suppressor genes in prostate cancer. Cancer 2010; 116: 5637–5649.
Mouillet JF, Chu T, Nelson DM, Mishima T, Sadovsky Y . MiR-205 silences MED1 in hypoxic primary human trophoblasts. FASEB J 2010; 24: 2030–2039.
Wang Q, Sharma D, Ren Y, Fondell JD . A coregulatory role for the TRAP-mediator complex in androgen receptor-mediated gene expression. J Biol Chem 2002; 277: 42852–42858.
Wang Q, Carroll JS, Brown M . Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol Cell 2005; 19: 631–642.
Kouzarides T . Chromatin modifications and their function. Cell 2007; 128: 693–705.
Damber JE, Aus G . Prostate cancer. Lancet 2008; 371: 1710–1721.
Vijayvargia R, May MS, Fondell JD . A coregulatory role for the mediator complex in prostate cancer cell proliferation and gene expression. Cancer Res 2007; 67: 4034–4041.
Belakavadi M, Pandey PK, Vijayvargia R, Fondell JD . MED1 phosphorylation promotes its association with mediator: implications for nuclear receptor signaling. Mol Cell Biol 2008; 28: 3932–3942.
Wiklund ED, Bramsen JB, Hulf T, Dyrskjot L, Ramanathan R, Hansen TB et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int J Cancer 2010; 128: 1327–1334.
Ke XS, Qu Y, Rostad K, Li WC, Lin B, Halvorsen OJ et al. Genome-wide profiling of histone h3 lysine 4 and lysine 27 trimethylation reveals an epigenetic signature in prostate carcinogenesis. PLoS ONE 2009; 4: e4687.
Karginov FV, Cheloufi S, Chong MM, Stark A, Smith AD, Hannon GJ . Diverse endonucleolytic cleavage sites in the mammalian transcriptome depend upon microRNAs, Drosha, and additional nucleases. Mol Cell 2010; 38: 781–788.
Koschubs T, Lorenzen K, Baumli S, Sandstrom S, Heck AJ, Cramer P . Preparation and topology of the Mediator middle module. Nucleic Acids Res 2010; 38: 3186–3195.
Zhu Y, Qi C, Jain S, Le Beau MM, Espinosa R, Atkins GB et al. Amplification and overexpression of peroxisome proliferator-activated receptor binding protein (PBP/PPARBP) gene in breast cancer. Proc Natl Acad Sci USA 1999; 96: 10848–10853.
Jia L, Coetzee GA . Androgen receptor-dependent PSA expression in androgen-independent prostate cancer cells does not involve androgen receptor occupancy of the PSA locus. Cancer Res 2005; 65: 8003–8008.
Paoletti AC, Parmely TJ, Tomomori-Sato C, Sato S, Zhu D, Conaway RC et al. Quantitative proteomic analysis of distinct mammalian Mediator complexes using normalized spectral abundance factors. Proc Natl Acad Sci USA 2006; 103: 18928–18933.
Kornberg RD . Mediator and the mechanism of transcriptional activation. Trends in Biochemsci 2005; 30: 235–239.
Platica M, Verma RS, Macera MJ, Platica O . LNCaP-OM, a new androgen-resistant prostate cancer subline. In Vitro Cell Dev Biol Anim 1997; 33: 147–149.
Devaney J, Stirzaker C, Qu W, Song JZ, Statham AL, Patterson KI et al. Epigenetic deregulation across 2q14.2 differentiates normal from prostate cancer and provides a regional panel of novel DNA methylation cancer biomarkers. Cancer Epidemiol Biomarkers Prev 2011; 20: 148–159.
Agirre X, Vilas-Zornoza A, Jimenez-Velasco A, Martin-Subero JI, Cordeu L, Garate L et al. Epigenetic silencing of the tumor suppressor microRNA Hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia. Cancer Res 2009; 69: 4443–4453.
Song JZ, Stirzaker C, Harrison J, Melki JR, Clark SJ . Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells. Oncogene 2002; 21: 1048–1061.
Coolen MW, Statham AL, Gardiner-Garden M, Clark SJ . Genomic profiling of CpG methylation and allelic specificity using quantitative high-throughput mass spectrometry: critical evaluation and improvements. Nucleic Acids Res 2007; 35: e119.
Clark SJ, Harrison J, Paul CL, Frommer M . High sensitivity mapping of methylated cytosines. Nucleic Acids Res 1994; 22: 2990–2997.
Coolen MW, Stirzaker C, Song JZ, Statham AL, Kassir Z, Moreno CS et al. Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity. Nat Cell Biol 2010; 12: 235–246.
Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433: 769–773.
Horvath LG, Henshall SM, Kench JG, Saunders DN, Lee CS, Golovsky D et al. Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro. Clin Cancer Res 2004; 10: 615–625.
Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402–408.
Acknowledgements
We would like to thank Gillian Lehrbach, Ann-Maree Haynes, Ruth Pe Benito and Clarisse Puno for technical assistance. This work is supported by Cancer Institute NSW (CINSW), Cure Cancer Australia fellowships (TH), and National Health and Medical Research Council and CINSW project grants (SJC).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website
Rights and permissions
About this article
Cite this article
Hulf, T., Sibbritt, T., Wiklund, E. et al. Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer. Oncogene 32, 2891–2899 (2013). https://doi.org/10.1038/onc.2012.300
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2012.300
Keywords
This article is cited by
-
MicroRNAs as biomarkers for prostate cancer prognosis: a systematic review and a systematic reanalysis of public data
British Journal of Cancer (2022)
-
Unveiling the ups and downs of miR-205 in physiology and cancer: transcriptional and post-transcriptional mechanisms
Cell Death & Disease (2020)
-
Prediction and Analysis of Skin Cancer Progression using Genomics Profiles of Patients
Scientific Reports (2019)
-
Proliferation-associated miRNAs-494, -205, -21 and -126 detected by in situ hybridization: expression and prognostic potential in breast carcinoma patients
Journal of Cancer Research and Clinical Oncology (2018)
-
Computational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in prostate cancer
Nature Communications (2017)