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.

DNA methylation variations are required for epithelial-to-mesenchymal transition induced by cancer-associated fibroblasts in prostate cancer cells

Oncogene volume 36, pages 5551–5566 (2017)Cite this article

Subjects

Abstract

Widespread genome hypo-methylation and promoter hyper-methylation of epithelium-specific genes are hallmarks of stable epithelial-to-mesenchymal transition (EMT), which in prostate cancer (PCa) correlates with castration resistance, cancer stem cells generation, chemoresistance and worst prognosis. Exploiting our consolidated ‘ex-vivo’ system, we show that cancer-associated fibroblasts (CAFs) released factors have pivotal roles in inducing genome methylation changes required for EMT and stemness in EMT-prone PCa cells. By global DNA methylation analysis and RNA-Seq, we provide compelling evidence that conditioned media from CAFs explanted from two unrelated patients with advanced PCa, stimulates concurrent DNA hypo- and hyper-methylation required for EMT and stemness in PC3 and DU145, but not in LN-CaP and its derivative C4-2B, PCa cells. CpG island (CGI) hyper-methylation associates with repression of genes required for epithelial maintenance and invasion antagonism, whereas activation of EMT markers and stemness genes correlate with CGI hypo-methylation. Remarkably, methylation variations and EMT-regulated transcripts almost completely reverse qualitatively and quantitatively during MET. Unsupervised clustering analysis of the PRAD TCGA data set with the differentially expressed (DE) and methylated EMT signature, identified a gene cluster of DE genes defined by a CAF+ and AR- phenotype and worst diagnosis. This gene cluster includes the relevant factors for EMT and stemness, which display DNA methylation variations in regulatory regions inversely correlated to their expression changes, thus strongly sustaining the ex-vivo data. DNMT3A-dependent methylation is essential for silencing epithelial maintenance and EMT counteracting genes, such as CDH1 and GRHL2, that is, the direct repressor of ZEB1, the key transcriptional factor for EMT and stemness. Accordingly, DNMT3A knock-down prevents EMT entry. These results shed light on the mechanisms of establishment and maintenance of coexisting DNA hypo- and hyper-methylation patterns during cancer progression, the generation of EMT and cell stemness in advanced PCa, and may pave the way to new therapeutic implications.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

EMT:

epithelial-to-mesenchymal transition

MET:

mesenchymal-to-epithelial transition

PCa:

prostate carcinoma

HPF:

fibroblasts from benign prostatic hyperplasia

CAF:

cancer-associated fibroblast

CM-HPF:

conditioned medium from fibroblasts from benign prostatic hyperplasia

CM-CAF:

conditioned medium from cancer-associated fibroblast

DE:

differentially expressed

DM:

differentially methylated

FC:

fold change

References

  1. Li P, Yang R, Gao WQ . Contributions of epithelial-mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer. Mol Cancer 2014; 13: 55.

    Article  Google Scholar 

  2. Cirri P, Chiarugi P . Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev 2012; 31: 195–208.

    Article  Google Scholar 

  3. Tam WL, Weinberg RA . The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 2013; 19: 1438–1449.

    Article  CAS  Google Scholar 

  4. Cieply B, Farris J, Denvir J, Ford HL, Frisch SM . Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2. Cancer Res 2013; 73: 6299–6309.

    Article  CAS  Google Scholar 

  5. Hong T, Watanabe K, Ta CH, Villarreal-Ponce A, Nie Q, Dai X . An Ovol2-Zeb1 mutual inhibitory circuit governs bidirectional and multi-step transition between epithelial and mesenchymal states. PLoS Comput Biol 2015; 11: e1004569.

    Article  Google Scholar 

  6. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 2015; 527: 472–476.

    Article  CAS  Google Scholar 

  7. Hollier BG, Evans K, Mani SA . The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 2009; 14: 29–43.

    Article  Google Scholar 

  8. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

    Article  CAS  Google Scholar 

  9. Steinestel K, Eder S, Schrader AJ, Steinestel J . Clinical significance of epithelial-mesenchymal transition. Clin Transl Med 2014; 3: 17.

    Article  Google Scholar 

  10. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015; 527: 525–530.

    Article  CAS  Google Scholar 

  11. Dumont N, Wilson MB, Crawford YG, Reynolds PA, Sigaroudinia M, Tlsty TD . Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci USA 2008; 105: 14867–14872.

    Article  CAS  Google Scholar 

  12. Malouf GG, Taube JH, Lu Y, Roysarkar T, Panjarian S, Estecio MR et al. Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition. Genome Biol 2013; 14: R144.

    Article  Google Scholar 

  13. McDonald OG, Wu H, Timp W, Doi A, Feinberg AP . Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nat Struct Mol Biol 2011; 18: 867–874.

    Article  CAS  Google Scholar 

  14. Cardenas H, Vieth E, Lee J, Segar M, Liu Y, Nephew KP et al. TGF-β induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells. Epigenetics 2014; 9: 1461–1472.

    Article  Google Scholar 

  15. Carmona FJ, Davalos V, Vidal E, Gomez A, Heyn H, Hashimoto Y et al. A comprehensive DNA methylation profile of epithelial-to-mesenchymal transition. Cancer Res 2014; 74: 5608–5619.

    Article  CAS  Google Scholar 

  16. Ke XS, Qu Y, Cheng Y, Li WC, Rotter V, Øyan AM et al. Global profiling of histone and DNA methylation reveals epigenetic-based regulation of gene expression during epithelial to mesenchymal transition in prostate cells. BMC Genomics 2010; 11: 669.

    Article  Google Scholar 

  17. Tai S, Sun Y, Squires JM, Zhang H, Oh WK, Liang CZ et al. PC3 is a cell line characteristic of prostatic small cell carcinoma. Prostate 2011; 71: 1668–1679.

    Article  CAS  Google Scholar 

  18. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res 2010; 70: 6945–6956.

    Article  CAS  Google Scholar 

  19. Giannoni E, Bianchini F, Calorini L, Chiarugi P . Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid Redox Signal 2011; 14: 2361–2371.

    Article  CAS  Google Scholar 

  20. Giannoni E, Taddei ML, Parri M, Bianchini F, Santosuosso M, Grifantini R et al. EphA2-mediated mesenchymal-amoeboid transition induced by endothelial progenitor cells enhances metastatic spread due to cancer-associated fibroblasts. J Mol Med (Berl) 2013; 91: 103–115.

    Article  CAS  Google Scholar 

  21. Taddei ML, Parri M, Angelucci A, Bianchini F, Marconi C, Giannoni E et al. EphA2 induces metastatic growth regulating amoeboid motility and clonogenic potential in prostate carcinoma cells. Mol Cancer Res 2011; 9: 149–160.

    Article  CAS  Google Scholar 

  22. Taddei ML, Cavallini L, Comito G, Giannoni E, Folini M, Marini A et al. Senescent stroma promotes prostate cancer progression: the role of miR-210. Mol Oncol 2014; 8: 1729–1746.

    Article  CAS  Google Scholar 

  23. Ohka F, Natsume A, Motomura K, Kishida Y, Kondo Y, Abe T et al. The global DNA methylation surrogate LINE-1 methylation is correlated with MGMT promoter methylation and is a better prognostic factor for glioma. PLoS One 2011; 6: e23332.

    Article  CAS  Google Scholar 

  24. Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest 2011; 121: 1064–1074.

    Article  CAS  Google Scholar 

  25. Warzecha CC, Sato TK, Nabet B, Hogenesch JB, Carstens RP . ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell 2009; 33: 591–601.

    Article  CAS  Google Scholar 

  26. Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 2014; 14: 342–356.

    Article  CAS  Google Scholar 

  27. Deaton AM, Bird A . CpG islands and the regulation of transcription. Genes Dev 2011; 25: 1010–1022.

    Article  CAS  Google Scholar 

  28. Cieply B, Riley P, Pifer PM, Widmeyer J, Addison JB, Ivanov AV et al. Suppression of the epithelial-mesenchymal transition by Grainyhead-like-2. Cancer Res 2012; 72: 2440–2453.

    Article  CAS  Google Scholar 

  29. Roca H, Hernandez J, Weidner S, McEachin RC, Fuller D, Sud S et al. Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS One 2013; 8: e76773.

    Article  CAS  Google Scholar 

  30. Aue A, Hinze C, Walentin K, Ruffert J, Yurtdas Y, Werth M et al. A grainyhead-like 2/Ovo-like 2 pathway regulates renal epithelial barrier function and lumen expansion. J Am Soc Nephrol 2015; 26: 2704–2715.

    Article  CAS  Google Scholar 

  31. Gascard P, Tlsty TD . Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev 2016; 30: 1002–1019.

    Article  CAS  Google Scholar 

  32. Vastenhouw NL, Schier AF . Bivalent histone modifications in early embryogenesis. Curr Opin Cell Biol 2012; 24: 374–386.

    Article  CAS  Google Scholar 

  33. Bernhart SH, Kretzmer H, Holdt LM, Jühling F, Ammerpohl O, Bergmann AK et al. Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer. Sci Rep 2016; 6: 37393.

    Article  CAS  Google Scholar 

  34. Rodriguez J, Muñoz M, Vives L, Frangou CG, Groudine M, Peinado MA . Bivalent domains enforce transcriptional memory of DNA methylated genes in cancer cells. Proc Natl Acad Sci USA 2008; 105: 19809–19814.

    Article  CAS  Google Scholar 

  35. Cui H, Wang L, Gong P, Zhao C, Zhang S, Zhang K et al. Deregulation between miR-29b/c and DNMT3 A is associated with epigenetic silencing of the CDH1 gene, affecting cell migration and invasion in gastric cancer. PLoS One 2015; 10: e0123926.

    Article  Google Scholar 

  36. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA 2007; 104: 15805–15810.

    Article  CAS  Google Scholar 

  37. Morita S, Horii T, Kimura M, Ochiya T, Tajima S, Hatada I . miR-29 represses the activities of DNA methyltransferases and DNA demethylases. Int J Mol Sci 2013; 14: 14647–14658.

    Article  Google Scholar 

  38. Ru P, Steele R, Newhall P, Phillips NJ, Toth K, Ray RB . miRNA-29b suppresses prostate cancer metastasis by regulating epithelial-mesenchymal transition signaling. Mol Cancer Ther 2012; 11: 1166–1173.

    Article  CAS  Google Scholar 

  39. García de Herreros A . Epithelial to mesenchymal transition in tumor cells as consequence of phenotypic instability. Front Cell Dev Biol 2014; 2: 71.

    PubMed  PubMed Central  Google Scholar 

  40. Yaqinuddin A, Qureshi SA, Qazi R, Abbas F . Down-regulation of DNMT3b in PC3 cells effects locus-specific DNA methylation, and represses cellular growth and migration. Cancer Cell Int 2008; 8: 13.

    Article  Google Scholar 

  41. Yaqinuddin A, Qureshi SA, Qazi R, Farooq S, Abbas F . DNMT1 silencing affects locus specific DNA methylation and increases prostate cancer derived PC3 cell invasiveness. J Urol 2009; 182: 756–761.

    Article  CAS  Google Scholar 

  42. Babbio F, Castiglioni I, Cassina C, Gariboldi MB, Pistore C, Magnani E et al. Knock-down of methyl CpG-binding protein 2 (MeCP2) causes alterations in cell proliferation and nuclear lamins expression in mammalian cells. BMC Cell Biol 2012; 13: 19.

    Article  CAS  Google Scholar 

  43. Bostick M, Kim JK, Estève PO, Clark A, Pradhan S, Jacobsen SE . UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 2007; 317: 1760–1764.

    Article  CAS  Google Scholar 

  44. Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo TA et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 2007; 450: 908–912.

    Article  CAS  Google Scholar 

  45. von Meyenn F, Iurlaro M, Habibi E, Liu NQ, Salehzadeh-Yazdi A, Santos F et al. Impairment of DNA Methylation Maintenance Is the Main Cause of Global Demethylation in Naive Embryonic Stem Cells. Mol Cell 2016; 62: 848–861.

    Article  CAS  Google Scholar 

  46. 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.

    Article  Google Scholar 

  47. Lu ZX, Huang Q, Park JW, Shen S, Lin L, Tokheim CJ et al. Transcriptome-wide landscape of pre-mRNA alternative splicing associated with metastatic colonization. Mol Cancer Res 2015; 13: 305–318.

    Article  CAS  Google Scholar 

  48. Preca BT, Bajdak K, Mock K, Sundararajan V, Pfannstiel J, Maurer J et al. A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells. Int J Cancer 2015; 137: 2566–2577.

    Article  CAS  Google Scholar 

  49. Warzecha CC, Shen S, Xing Y, Carstens RP . The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events. RNA Biol 2009; 6: 546–562.

    Article  CAS  Google Scholar 

  50. Parpart S, Roessler S, Dong F, Rao V, Takai A, Ji J et al. Modulation of miR-29 expression by α-fetoprotein is linked to the hepatocellular carcinoma epigenome. Hepatology 2014; 60: 872–883.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  52. Schubert M, Spahn M, Kneitz S, Scholz CJ, Joniau S, Stroebel P et al. Distinct microRNA expression profile in prostate cancer patients with early clinical failure and the impact of let-7 as prognostic marker in high-risk prostate cancer. PLoS One 2013; 8: e65064.

    Article  CAS  Google Scholar 

  53. Liu F, Zhou Y, Zhou D, Kan M, Niu X, Zhang Z et al. Whole DNA methylome profiling in lung cancer cells before and after epithelial-to-mesenchymal transition. Diagn Pathol 2014; 9: 66.

    Article  Google Scholar 

  54. Scheel C, Weinberg RA . Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol 2012; 22: 396–403.

    Article  CAS  Google Scholar 

  55. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 2015; 12: 445–464.

    Article  CAS  Google Scholar 

  56. Zhang P, Sun Y, Ma L . ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle 2015; 14: 481–487.

    Article  CAS  Google Scholar 

  57. Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 2013; 154: 61–74.

    Article  CAS  Google Scholar 

  58. Zhang P, Wei Y, Wang L, Debeb BG, Yuan Y, Zhang J et al. ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nat Cell Biol 2014; 16: 864–875.

    Article  CAS  Google Scholar 

  59. Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 2007; 26: 6979–6988.

    Article  CAS  Google Scholar 

  60. Cheung AK, Ip JC, Chu AC, Cheng Y, Leong MM, Ko JM et al. PTPRG suppresses tumor growth and invasion via inhibition of Akt signaling in nasopharyngeal carcinoma. Oncotarget 2015; 6: 13434–13447.

    Article  Google Scholar 

  61. Nogales V, Reinhold WC, Varma S, Martinez-Cardus A, Moutinho C, Moran S et al. Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs. Oncotarget 2016; 7: 3084–3097.

    Article  Google Scholar 

  62. Krisenko MO, Geahlen RL . Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer. Biochim Biophys Acta 2015; 1853: 254–263.

    Article  CAS  Google Scholar 

  63. Bhatt T, Rizvi A, Batta SP, Kataria S, Jamora C . Signaling and mechanical roles of E-cadherin. Cell Commun Adhes 2013; 20: 189–199.

    Article  CAS  Google Scholar 

  64. Lee B, Villarreal-Ponce A, Fallahi M, Ovadia J, Sun P, Yu QC et al. Transcriptional mechanisms link epithelial plasticity to adhesion and differentiation of epidermal progenitor cells. Dev Cell 2014; 29: 47–58.

    Article  Google Scholar 

  65. Marinkovich MP, Taylor TB, Keene DR, Burgeson RE, Zone JJ . LAD-1, the linear IgA bullous dermatosis autoantigen, is a novel 120-kDa anchoring filament protein synthesized by epidermal cells. J Invest Dermatol 1996; 106: 734–738.

    Article  CAS  Google Scholar 

  66. Guo M, Liu W, Serra S, Asa SL, Ezzat S . FGFR2 isoforms support epithelial-stromal interactions in thyroid cancer progression. Cancer Res 2012; 72: 2017–2027.

    Article  CAS  Google Scholar 

  67. Grega-Larson NE, Crawley SW, Erwin AL, Tyska MJ . Cordon bleu promotes the assembly of brush border microvilli. Mol Biol Cell 2015; 26: 3803–3815.

    Article  CAS  Google Scholar 

  68. Yang L, Chen Y, Cui T, Knösel T, Zhang Q, Albring KF et al. Desmoplakin acts as a tumor suppressor by inhibition of the Wnt/β-catenin signaling pathway in human lung cancer. Carcinogenesis 2012; 33: 1863–1870.

    Article  CAS  Google Scholar 

  69. Zhang Y, Yeh LK, Zhang S, Call M, Yuan Y, Yasunaga M et al. Wnt/β-catenin signaling modulates corneal epithelium stratification via inhibition of Bmp4 during mouse development. Development 2015; 142: 3383–3393.

    Article  CAS  Google Scholar 

  70. Kgatle MM, Kalla AA, Islam MM, Sathekge M, Moorad R . Prostate cancer: epigenetic alterations, risk factors, and therapy. Prostate Cancer 2016; 2016: 5653862.

    Article  Google Scholar 

  71. Liang G, Chan MF, Tomigahara Y, Tsai YC, Gonzales FA, Li E et al. Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol 2002; 22: 480–491.

    Article  CAS  Google Scholar 

  72. Ficz G . New insights into mechanisms that regulate DNA methylation patterning. J Exp Biol 2015; 218: 14–20.

    Article  Google Scholar 

  73. Spans L, Helsen C, Clinckemalie L, Van den Broeck T, Prekovic S, Joniau S et al. Comparative genomic and transcriptomic analyses of LNCaP and C4-2B prostate cancer cell lines. PLoS One 2014; 9: e90002.

    Article  Google Scholar 

  74. Lawlor H, Meunier A, McDermott N, Lynch TH, Marignol L . Identification of suitable endogenous controls for gene and miRNA expression studies in irradiated prostate cancer cells. Tumour Biol 2015; 36: 6019–6028.

    Article  CAS  Google Scholar 

  75. Sauer E, Babion I, Madea B, Courts C . An evidence based strategy for normalization of quantitative PCR data from miRNA expression analysis in forensic organ tissue identification. Forensic Sci Int Genet 2014; 13: 217–223.

    Article  CAS  Google Scholar 

  76. Babbio F, Pistore C, Curti L, Castiglioni I, Kunderfranco P, Brino L et al. The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression. Oncogene 2012; 31: 4878–4887.

    Article  CAS  Google Scholar 

  77. Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 2012; 7: 562–578.

    Article  CAS  Google Scholar 

  78. Anders S, Pyl PT, Huber W . HTSeq—a python framework to work with high-throughput sequencing data. Bioinformatics 2015; 31: 166–169.

    Article  CAS  Google Scholar 

  79. Stefanoli M, La Rosa S, Sahnane N, Romualdi C, Pastorino R, Marando A et al. Prognostic relevance of aberrant DNA methylation in g1 and g2 pancreatic neuroendocrine tumors. Neuroendocrinology 2014; 100: 26–34.

    Article  CAS  Google Scholar 

  80. Hur K, Toiyama Y, Takahashi M, Balaguer F, Nagasaka T, Koike J et al. MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut 2013; 62: 1315–1326.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Epigenomics Flagship Project (EPIGEN-CNR-IT: to IMB, VC, DF and AW); Italian Association for Cancer Research (AIRC: grants IG-8797 to PC and IG-17426 to AW). TC is now supported by a three year AIRC fellowship (Project code: 19548). The Ethics approval and consent to participate at the study named ‘Ruolo del microambiente stromale nella immunomodulazione e nella progression del carcinoma prostatico (Role of the stromal microenvironment for immunomodulation and for cancer progression in prostatic carcinoma)’ was released with reference number ‘BIO 15.016’ from the Ethics committee ‘Area Vasta Centro’ of the 'Azienda Ospedaliera Universitaria Correggi' in Florence—Italy on the 26th of June 2015.

Author information

Author notes

  1. T Colangelo

    Present address: 9Current address: Institute for Stem cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Casa Sollievo della Sofferenza-IRCCS, San Giovanni Rotondo, Italy.,

  2. C Pistore, E Giannoni, T Colangelo and F Rizzo: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Biotechnology and Life Sciences, University of Insubria, Busto Arsizio (VA), Italy

    C Pistore, E Magnani, M Mancini, S Rizzo, M Riccardi, M Mandruzzato, F Macchi & I M Bonapace

  2. Department of Biomedical, Experimental and Clinical Sciences ‘Mario Serio’, University of Florence, Florence, Italy

    E Giannoni & P Chiarugi

  3. Department of Sciences and Technologies, University of Sannio, Benevento, Italy

    T Colangelo, L Muccillo & V Colantuoni

  4. Department of Medicine, Laboratory of Molecular Medicine and Genomics, Surgery and Dentistry ‘Schola Medica Salernitana’, University of Salerno, Baronissi (SA), Italy

    F Rizzo, G Giurato & A Weisz

  5. Department of Surgical and Morphologic Sciences, Anatomic Pathology Unit, University of Insubria, Varese, Italy

    N Sahnane & D Furlan

  6. Centre for Genomic Sciences, Italian Institute of Technology, Milan, Italy

    K Kishore & M Pelizzola

  7. Centre for Integrative Biology, University of Trento, Trento, Italy

    V Del Vescovo & M A Denti

Authors
  1. C Pistore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Giannoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Colangelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Magnani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L Muccillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Giurato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Mancini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Riccardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N Sahnane
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. V Del Vescovo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. K Kishore
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M Mandruzzato
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. F Macchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M Pelizzola
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. M A Denti
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. D Furlan
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. A Weisz
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. V Colantuoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. P Chiarugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. I M Bonapace
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I M Bonapace.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pistore, C., Giannoni, E., Colangelo, T. et al. DNA methylation variations are required for epithelial-to-mesenchymal transition induced by cancer-associated fibroblasts in prostate cancer cells. Oncogene 36, 5551–5566 (2017). https://doi.org/10.1038/onc.2017.159

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.159

Search

Advanced search

Quick links