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The histone demethylase KDM3A is a microRNA-22-regulated tumor promoter in Ewing Sarcoma

Oncogene volume 34, pages 257–262 (2015)Cite this article

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Abstract

Ewing Sarcoma is a biologically aggressive bone and soft tissue malignancy affecting children and young adults. Ewing Sarcoma pathogenesis is driven by EWS/Ets fusion oncoproteins, of which EWS/Fli1 is the most common. We have previously shown that microRNAs (miRs) regulated by EWS/Fli1 contribute to the pro-oncogenic program in Ewing Sarcoma. Here we show that miR-22, an EWS/Fli1-repressed miR, is inhibitory to Ewing Sarcoma clonogenic and anchorage-independent cell growth, even at modest overexpression levels. Our studies further identify the H3K9me1/2 histone demethylase KDM3A (JMJD1A/JHDM2A) as a new miR-22-regulated gene. We show that KDM3A is overexpressed in Ewing Sarcoma, and that its depletion inhibits clonogenic and anchorage-independent growth in multiple patient-derived cell lines, and tumorigenesis in a xenograft model. KDM3A depletion further results in augmentation of the levels of the repressive H3K9me2 histone mark, and downregulation of pro-oncogenic factors in Ewing Sarcoma. Together, our studies identify the histone demethylase KDM3A as a new, miR-regulated, tumor promoter in Ewing Sarcoma.

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References

  1. Ludwig JA . Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr Opin Oncol 2008; 20: 412–418.

    Article  Google Scholar 

  2. Toomey EC, Schiffman JD, Lessnick SL . Recent advances in the molecular pathogenesis of Ewing's sarcoma. Oncogene 2010; 29: 4504–4516.

    Article  CAS  Google Scholar 

  3. Ghildiyal M, Zamore PD . Small silencing RNAs: an expanding universe. Nat Rev Genet 2009; 10: 94–108.

    Article  CAS  Google Scholar 

  4. Sotiropoulou G, Pampalakis G, Lianidou E, Mourelatos Z . Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell. RNA 2009; 15: 1443–1461.

    Article  CAS  Google Scholar 

  5. Kasinski AL, Slack FJ . Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer 2011; 11: 849–864.

    Article  CAS  Google Scholar 

  6. McKinsey EL, Parrish JK, Irwin AE, Niemeyer BF, Kern HB, Birks DK et al. A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs. Oncogene 2011; 30: 4910–4920.

    Article  CAS  Google Scholar 

  7. Ban J, Jug G, Mestdagh P, Schwentner R, Kauer M, Aryee DN et al. Hsa-mir-145 is the top EWS-FLI1-repressed microRNA involved in a positive feedback loop in Ewing's sarcoma. Oncogene 2011; 30: 2173–2180.

    Article  CAS  Google Scholar 

  8. De Vito C, Riggi N, Suva ML, Janiszewska M, Horlbeck J, Baumer K et al. Let-7a is a direct EWS-FLI-1 target implicated in Ewing's sarcoma development. PLoS One 2011; 6: e23592.

    Article  CAS  Google Scholar 

  9. Franzetti GA, Laud-Duval K, Bellanger D, Stern MH, Sastre-Garau X, Delattre O . MiR-30a-5p connects EWS-FLI1 and CD99, two major therapeutic targets in Ewing tumor. Oncogene 2012; 32: 3915–3921.

    Article  Google Scholar 

  10. Nakatani F, Ferracin M, Manara MC, Ventura S, Del Monaco V, Ferrari S et al. miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy. J Pathol 2012; 226: 796–805.

    Article  CAS  Google Scholar 

  11. Baylin SB, Jones PA . A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 2011; 11: 726–734.

    Article  CAS  Google Scholar 

  12. Ryan RJ, Bernstein BE . Molecular biology. Genetic events that shape the cancer epigenome. Science 2012; 336: 1513–1514.

    Article  CAS  Google Scholar 

  13. Lawlor ER, Thiele CJ . Epigenetic changes in pediatric solid tumors: promising new targets. Clin Cancer Res 2012; 18: 2768–2779.

    Article  CAS  Google Scholar 

  14. Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 2012; 481: 329–334.

    Article  CAS  Google Scholar 

  15. Li J, Liang S, Yu H, Zhang J, Ma D, Lu X . An inhibitory effect of miR-22 on cell migration and invasion in ovarian cancer. Gynecol Oncol 2010; 119: 543–548.

    Article  CAS  Google Scholar 

  16. Li J, Zhang Y, Zhao J, Kong F, Chen Y . Overexpression of miR-22 reverses paclitaxel-induced chemoresistance through activation of PTEN signaling in p53-mutated colon cancer cells. Mol Cell Biochem 2011; 357: 31–38.

    Article  CAS  Google Scholar 

  17. Nagaraja AK, Creighton CJ, Yu Z, Zhu H, Gunaratne PH, Reid JG et al. A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. Mol Endocrinol 2010; 24: 447–463.

    Article  CAS  Google Scholar 

  18. Patel JB, Appaiah HN, Burnett RM, Bhat-Nakshatri P, Wang G, Mehta R et al. Control of EVI-1 oncogene expression in metastatic breast cancer cells through microRNA miR-22. Oncogene 2011; 30: 1290–1301.

    Article  CAS  Google Scholar 

  19. Ting Y, Medina DJ, Strair RK, Schaar DG . Differentiation-associated miR-22 represses Max expression and inhibits cell cycle progression. Biochem Biophys Res Commun 2010; 394: 606–611.

    Article  CAS  Google Scholar 

  20. Xiong J, Du Q, Liang Z . Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein. Oncogene 2010; 29: 4980–4988.

    Article  CAS  Google Scholar 

  21. Xiong J, Yu D, Wei N, Fu H, Cai T, Huang Y et al. An estrogen receptor alpha suppressor, microRNA-22, is downregulated in estrogen receptor alpha-positive human breast cancer cell lines and clinical samples. FEBS J 2010; 277: 1684–1694.

    Article  CAS  Google Scholar 

  22. Zhang J, Yang Y, Yang T, Liu Y, Li A, Fu S et al. microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer 2010; 103: 1215–1220.

    Article  CAS  Google Scholar 

  23. Gurtan AM, Sharp PA . The role of miRNAs in regulating gene expression networks. J Mol Biol 2013; 425: 3582–3600.

    Article  CAS  Google Scholar 

  24. Riggi N, Cironi L, Provero P, Suva ML, Kaloulis K, Garcia-Echeverria C et al. Development of Ewing's sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res 2005; 65: 11459–11468.

    Article  CAS  Google Scholar 

  25. Riggi N, Suva ML, Suva D, Cironi L, Provero P, Tercier S et al. EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells. Cancer Res 2008; 68: 2176–2185.

    Article  CAS  Google Scholar 

  26. Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O . Mesenchymal stem cell features of Ewing tumors. Cancer Cell 2007; 11: 421–429.

    Article  CAS  Google Scholar 

  27. Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 2006; 125: 483–495.

    Article  CAS  Google Scholar 

  28. Cloos PA, Christensen J, Agger K, Helin K . Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev 2008; 22: 1115–1140.

    Article  CAS  Google Scholar 

  29. Li B, Carey M, Workman JL . The role of chromatin during transcription. Cell 2007; 128: 707–719.

    Article  CAS  Google Scholar 

  30. Wai DH, Schaefer KL, Schramm A, Korsching E, Van Valen F, Ozaki T et al. Expression analysis of pediatric solid tumor cell lines using oligonucleotide microarrays. Int J Oncol 2002; 20: 441–451.

    CAS  PubMed  Google Scholar 

  31. Cho HS, Toyokawa G, Daigo Y, Hayami S, Masuda K, Ikawa N et al. The JmjC domain-containing histone demethylase KDM3A is a positive regulator of the G1/S transition in cancer cells via transcriptional regulation of the HOXA1 gene. Int J Cancer 2012; 131: E179–E189.

    Article  CAS  Google Scholar 

  32. Chen H, Kluz T, Zhang R, Costa M . Hypoxia and nickel inhibit histone demethylase JMJD1A and repress Spry2 expression in human bronchial epithelial BEAS-2B cells. Carcinogenesis 2010; 31: 2136–2144.

    Article  CAS  Google Scholar 

  33. Mimura I, Nangaku M, Kanki Y, Tsutsumi S, Inoue T, Kohro T et al. Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol Cell Biol 2012; 32: 3018–3032.

    Article  CAS  Google Scholar 

  34. Richter GH, Plehm S, Fasan A, Rossler S, Unland R, Bennani-Baiti IM et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc Natl Acad Sci USA 2009; 106: 5324–5329.

    Article  CAS  Google Scholar 

  35. Douglas D, Hsu JH, Hung L, Cooper A, Abdueva D, van Doorninck J et al. BMI-1 promotes ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res 2008; 68: 6507–6515.

    Article  CAS  Google Scholar 

  36. Patel M, Simon JM, Iglesia MD, Wu SB, McFadden AW, Lieb JD et al. Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription. Genome Res 2012; 22: 259–270.

    Article  CAS  Google Scholar 

  37. Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC et al. The genetic landscape of the childhood cancer medulloblastoma. Science 2011; 331: 435–439.

    CAS  Google Scholar 

  38. Geutjes EJ, Bajpe PK, Bernards R . Targeting the epigenome for treatment of cancer. Oncogene 2012; 31: 3827–3844.

    Article  CAS  Google Scholar 

  39. Erkizan HV, Kong Y, Merchant M, Schlottmann S, Barber-Rotenberg JS, Yuan L et al. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat Med 2009; 15: 750–756.

    Article  CAS  Google Scholar 

  40. Grohar PJ, Woldemichael GM, Griffin LB, Mendoza A, Chen QR, Yeung C et al. Identification of an inhibitor of the EWS-FLI1 oncogenic transcription factor by high-throughput screening. J Natl Cancer Inst 2011; 103: 962–978.

    Article  CAS  Google Scholar 

  41. Greer EL, Shi Y . Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 2012; 13: 343–357.

    Article  CAS  Google Scholar 

  42. Fukuma M, Okita H, Hata J, Umezawa A . Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma. Oncogene 2003; 22: 1–9.

    Article  CAS  Google Scholar 

  43. Shirato H, Ogawa S, Nakajima K, Inagawa M, Kojima M, Tachibana M et al. A jumonji (Jarid2) protein complex represses cyclin D1 expression by methylation of histone H3-K9. J Biol Chem 2009; 284: 733–739.

    Article  CAS  Google Scholar 

  44. Cittelly DM, Dimitrova I, Howe EN, Cochrane DR, Jean A, Spoelstra NS et al. Restoration of miR-200c to ovarian cancer reduces tumor burden and increases sensitivity to paclitaxel. Mol Cancer Ther 2012; 11: 2556–2565.

    Article  CAS  Google Scholar 

  45. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098–1101.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Kathrin Bernt and Tobias Neff for advice on histone mark analysis, Steve Lessnick for retroviral packaging constructs, Heide Ford for critical reading of the manuscript, and the University of Colorado Cancer Center DNA Sequencing, Flow Cytometry, and Functional Genomics core facilities. This work was supported by the Boettcher Foundation’s Webb-Waring Biomedical Research Program, Department of Defense Discovery Award (W81XWH-12-1-0296), Alex’s Lemonade Stand Foundation for Childhood Cancer, and funds from the University of Colorado School of Medicine and Cancer Center (to PJ); and Merit Award from the US Department of Veterans’ Affairs and R01CA138528-2522717 (to RAW).

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Authors and Affiliations

  1. Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA

    J K Parrish & P Jedlicka

  2. Cancer Biology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA

    M Sechler & P Jedlicka

  3. Department of Medicine, University of Illinois, Chicago, IL, USA

    R A Winn

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Parrish, J., Sechler, M., Winn, R. et al. The histone demethylase KDM3A is a microRNA-22-regulated tumor promoter in Ewing Sarcoma. Oncogene 34, 257–262 (2015). https://doi.org/10.1038/onc.2013.541

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