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Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer

Oncogene volume 31, pages 1034–1044 (2012)Cite this article

Abstract

The human POK family members are transcription factors with a POZ domain and zinc-fingers that act primarily as transcriptional repressors. Several members of this family are involved in oncogenesis and this prompted us to assess whether expression levels of individual POK family members are associated with clinical outcomes in cancer. We have observed that ZBTB4 (zinc-finger and BTB domain containing 4) is downregulated in breast cancer patients, and that its expression is significantly correlated with relapse-free survival. Further integrative analysis of mRNA and microRNA (miR) expression data from the NCI-60 cell lines revealed an inverse correlation between ZBTB4 and oncogenic miRs derived from the miR-17-92 cluster and its paralogs. The experimental results using MDA-MB-231 and MCF-7 human breast cancer cells confirm that miRNAs derived from these clusters, containing miR-17-5p, miR-20a, miR-106a, miR-106b and miR-93, negatively regulate ZBTB4 expression. Overexpression of ZBTB4 or restoration of ZBTB4 by using an antagomir inhibit growth and invasion of breast cancer cells, and this effect is due, in part, to ZBTB4-dependent repression of the specificity protein 1 (Sp1), Sp3 and Sp4 genes, and subsequent downregulation of several Sp-dependent oncogenes, in part, through competition between ZBTB4 and Sp transcription factors for GC-rich promoter sequences. These results confirm that ZBTB4 functions as a novel tumor-suppressor gene with prognostic significance for breast cancer survival, and the oncogenic miR-17-92/ZBTB4/Sp axis may be a potential therapeutic target.

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References

  • Abdelrahim M, Baker CH, Abbruzzese JL, Sheikh-Hamad D, Liu S, Cho SD et al. (2007). Regulation of vascular endothelial growth factor receptor-1 (VEGFR1) expression by specificity proteins 1, 3 and 4 in pancreatic cancer cells. Cancer Res 67: 3286–3294.

    Article  CAS  Google Scholar 

  • Abdelrahim M, Samudio I, Smith R, Burghardt R, Safe S . (2002). Small inhibitory RNA duplexes for Sp1 mRNA block basal and estrogen-induced gene expression and cell cycle progression in MCF-7 breast cancer cells. J Biol Chem 277: 28815–28822.

    Article  CAS  Google Scholar 

  • Abdelrahim M, Smith III R, Burghardt R, Safe S . (2004). Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res 64: 6740–6749.

    Article  CAS  Google Scholar 

  • 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 tumor subtype. Genome Biol 8: R214.

    Article  Google Scholar 

  • Blower PE, Verducci JS, Lin S, Zhou J, Chung JH, Dai Z et al. (2007). MicroRNA expression profiles for the NCI-60 cancer cell panel. Mol Cancer Ther 6: 1483–1491.

    Article  CAS  Google Scholar 

  • Cattoretti G, Pasqualucci L, Ballon G, Tam W, Nandula SV, Shen Q et al. (2005). Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 7: 445–455.

    Article  CAS  Google Scholar 

  • Chadalapaka G, Jutooru I, Burghardt R, Safe S . (2010). Drugs that target specificity proteins downregulate epidermal growth factor receptor in bladder cancer cells. Mol Cancer Res 8: 739–750.

    Article  CAS  Google Scholar 

  • Chadalapaka G, Jutooru I, Chintharlapalli S, Papineni S, Smith III R, Li X et al. (2008). Curcumin decreases specificity protein expression in bladder cancer cells. Cancer Res 68: 5345–5354.

    Article  CAS  Google Scholar 

  • Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB . (2005). Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123: 437–448.

    Article  CAS  Google Scholar 

  • Chen WY, Zeng X, Carter MG, Morrell CN, Chiu Yen RW, Esteller M et al. (2003). Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet 33: 197–202.

    Article  CAS  Google Scholar 

  • Costoya JA . (2007). Functional analysis of the role of POK transcriptional repressors. Brief Funct Genomic Proteomic 6: 8–18.

    Article  CAS  Google Scholar 

  • Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E et al. (2006). Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 38: 1060–1065.

    Article  CAS  Google Scholar 

  • Eisen MB, Spellman PT, Brown PO, Botstein D . (1998). Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95: 14863–14868.

    Article  CAS  Google Scholar 

  • Filion GJ, Zhenilo S, Salozhin S, Yamada D, Prokhortchouk E, Defossez PA . (2006). A family of human zinc finger proteins that bind methylated DNA and repress transcription. Mol Cell Biol 26: 169–181.

    Article  CAS  Google Scholar 

  • Fontana L, Fiori ME, Albini S, Cifaldi L, Giovinazzi S, Forloni M et al. (2008). Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS One 3: e2236.

    Article  Google Scholar 

  • He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S et al. (2005). A microRNA polycistron as a potential human oncogene. Nature 435: 828–833.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Inomata M, Tagawa H, Guo YM, Kameoka Y, Takahashi N, Sawada K . (2009). MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes. Blood 113: 396–402.

    Article  CAS  Google Scholar 

  • Jeon BN, Choi WI, Yu MY, Yoon AR, Kim MH, Yun CO et al. (2009). ZBTB2, a novel master regulator of the p53 pathway. J Biol Chem 284: 17935–17946.

    Article  CAS  Google Scholar 

  • Jeon BN, Yoo JY, Choi WI, Lee CE, Yoon HG, Hur MW . (2008). Proto-oncogene FBI-1 (Pokemon/ZBTB7A) represses transcription of the tumor suppressor Rb gene via binding competition with Sp1 and recruitment of co-repressors. J Biol Chem 283: 33199–33210.

    Article  CAS  Google Scholar 

  • Jutooru I, Chadalapaka G, Abdelrahim M, Basha MR, Samudio I, Konopleva M et al. (2010). Methyl 2-Cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) decreases specificity protein (Sp) transcription factors and inhibits pancreatic tumor growth: role of microRNA-27a. Mol Pharmacol 78: 226–236.

    Article  CAS  Google Scholar 

  • Koh DI, Choi WI, Jeon BN, Lee CE, Yun CO, Hur MW . (2009). A novel POK family transcription factor, ZBTB5, represses transcription of p21CIP1 gene. J Biol Chem 284: 19856–19866.

    Article  CAS  Google Scholar 

  • Kojima S, Hatano M, Okada S, Fukuda T, Toyama Y, Yuasa S et al. (2001). Testicular germ cell apoptosis in Bcl6-deficient mice. Development 128: 57–65.

    CAS  PubMed  Google Scholar 

  • Koutsodontis G, Moustakas A, Kardassis D . (2002). The role of Sp1 family members, the proximal GC-rich motifs, and the upstream enhancer region in the regulation of the human cell cycle inhibitor p21WAF−1/Cip1 gene promoter. Biochemistry 41: 12771–12784.

    Article  CAS  Google Scholar 

  • Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ et al. (2005). Combinatorial microRNA target predictions. Nat Genet 37: 495–500.

    Article  CAS  Google Scholar 

  • Lee SO, Abdelrahim M, Yoon K, Chintharlapalli S, Papineni S, Kim K et al. (2010). Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth. Cancer Res 70: 6824–6836.

    Article  CAS  Google Scholar 

  • Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H et al. (2008). Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359: 2313–2323.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Li H, Bian C, Liao L, Li J, Zhao RC . (2011). miR-17-5p promotes human breast cancer cell migration and invasion through suppression of HBP1. Breast Cancer Res Treat 126: 565–575.

    Article  CAS  Google Scholar 

  • Liu H, D'Andrade P, Fulmer-Smentek S, Lorenzi P, Kohn KW, Weinstein JN et al. (2010). mRNA and microRNA expression profiles of the NCI-60 integrated with drug activities. Mol Cancer Ther 9: 1080–1091.

    Article  CAS  Google Scholar 

  • Liu S, Goldstein RH, Scepansky EM, Rosenblatt M . (2009). Inhibition of rho-associated kinase signaling prevents breast cancer metastasis to human bone. Cancer Res 69: 8742–8751.

    Article  CAS  Google Scholar 

  • Maeda T, Hobbs RM, Merghoub T, Guernah I, Zelent A, Cordon-Cardo C et al. (2005). Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433: 278–285.

    Article  CAS  Google Scholar 

  • Mertens-Talcott SU, Chintharlapalli S, Li X, Safe S . (2007). The oncogenic microRNA-27a targets genes that regulate specificity protein (Sp) transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res 67: 11001–11011.

    Article  CAS  Google Scholar 

  • Nicolas M, Noe V, Jensen KB, Ciudad CJ . (2001). Cloning and characterization of the 5′-flanking region of the human transcription factor Sp1 gene. J Biol Chem 276: 22126–22132.

    Article  CAS  Google Scholar 

  • Niu H . (2002). The proto-oncogene BCL-6 in normal and malignant B cell development. Hematol Oncol 20: 155–166.

    Article  Google Scholar 

  • Oh DS, Troester MA, Usary J, Hu Z, He X, Fan C et al. (2006). Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. J Clin Oncol 24: 1656–1664.

    Article  CAS  Google Scholar 

  • Pendergrast PS, Wang C, Hernandez N, Huang S . (2002). FBI-1 can stimulate HIV-1 Tat activity and is targeted to a novel subnuclear domain that includes the Tat-P-TEFb-containing nuclear speckles. Mol Biol Cell 13: 915–929.

    Article  CAS  Google Scholar 

  • Perez-Torrado R, Yamada D, Defossez PA . (2006). Born to bind: the BTB protein-protein interaction domain. Bioessays 28: 1194–1202.

    Article  CAS  Google Scholar 

  • Sasai N, Nakao M, Defossez PA . (2010). Sequence-specific recognition of methylated DNA by human zinc-finger proteins. Nucleic Acids Res 38: 5015–5022.

    Article  CAS  Google Scholar 

  • Shankavaram UT, Reinhold WC, Nishizuka S, Major S, Morita D, Chary KK et al. (2007). Transcript and protein expression profiles of the NCI-60 cancer cell panel: an integromic microarray study. Mol Cancer Ther 6: 820–832.

    Article  CAS  Google Scholar 

  • Takeuchi T, Tomida S, Yatabe Y, Kosaka T, Osada H, Yanagisawa K et al. (2006). Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors. J Clin Oncol 24: 1679–1688.

    Article  CAS  Google Scholar 

  • Tapias A, Ciudad CJ, Noe V . (2008). Transcriptional regulation of the 5′-flanking region of the human transcription factor Sp3 gene by NF-1, c-Myb, B-Myb, AP-1 and E2F. Biochim Biophys Acta 1779: 318–329.

    Article  CAS  Google Scholar 

  • Tillotson LG . (1999). RIN ZF, a novel zinc finger gene, encodes proteins that bind to the CACC element of the gastrin promoter. J Biol Chem 274: 8123–8128.

    Article  CAS  Google Scholar 

  • van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW et al. (2002). A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347: 1999–2009.

    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  Google Scholar 

  • Weber A, Marquardt J, Elzi D, Forster N, Starke S, Glaum A et al. (2008). Zbtb4 represses transcription of P21CIP1 and controls the cellular response to p53 activation. EMBO J 27: 1563–1574.

    Article  CAS  Google Scholar 

  • Yu Z, Wang C, Wang M, Li Z, Casimiro MC, Liu M et al. (2008). A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. J Cell Biol 182: 509–517.

    Article  CAS  Google Scholar 

  • Yu Z, Willmarth NE, Zhou J, Katiyar S, Wang M, Liu Y et al. (2010). microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling. Proc Natl Acad Sci USA 107: 8231–8236.

    Article  CAS  Google Scholar 

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Acknowledgements

This research was supported by the National Institutes of Health (CA136571) and is gratefully acknowledged. PAD is supported by Association pour la Recherche sur le Cancer, Ligue contre le Cancer and Institut National du Cancer. DY was supported by a postdoctoral fellowship from Association pour la Recherche sur le Cancer.

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Authors and Affiliations

  1. Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA

    K Kim, S-O Lee & S Safe

  2. Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA

    G Chadalapaka & S Safe

  3. CNRS UMR7216, Université Paris 7, Bâtiment Lamarck, Paris, France

    D Yamada & P-A Defossez

  4. Tumor Biology Department, Institut Curie, Paris, France

    X Sastre-Garau

  5. Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Y-Y Park & J-S Lee

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  1. K Kim
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Correspondence to S Safe.

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Kim, K., Chadalapaka, G., Lee, SO. et al. Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer. Oncogene 31, 1034–1044 (2012). https://doi.org/10.1038/onc.2011.296

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