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Transcription factor Sp1 is necessary and functional in regulating expression of oncogene ZNF703

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Abstract

Zinc finger protein 703 (ZNF703) is a putative oncogene in patients with the luminal B molecular subtype of breast cancer. Although the exact function of ZNF703 protein remains largely unknown, its expression and regulation have been implicated in several physiological and pathological processes. In the current study, for the first time, we identified and characterized the human ZNF703 gene promoter region. As a means of characterizing the transcription elements required for expression of ZNF703 protein at different stages, we cloned the promoter region of ZNF703 then created chimeric reporter plasmids for use in luciferase assays. A progressive deletion analysis of the ZNF703 gene’s 5′ and 3′ -flanking regions revealed that the core promoter is located in a 256-bp region ranging from nt-539 to nt-283. Next, we examined the effects of site-specific mutations and treatment with mithramycin A to identify the functional Sp1 binding site, which was found to be located in a 447 bp region that ranged from nt-509 to nt-76, displayed the characteristics of a CpG island, and overlapped with the promoter region. In conclusion, our data suggest that ZNF703 transcription is regulated by transcription factor Sp1. This finding should facilitate future studies of the mechanism which regulates expression of this important gene.

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Abbreviations

ANOVA:

Analysis of variance

References

  • Bazarov AV, Yaswen P (2011) Who is in the driver’s seat in 8p12 amplifications? ZNF703 in luminal B breast tumors. Breast Cancer Res 13:308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briggs MR, Kadonaga JT, Bell SP, Tjian R (1986) Purification and biochemical characterization of the promoter- specific transcription factor, Sp1. Science 234:47–52

    Article  CAS  PubMed  Google Scholar 

  • Bucher P (1990) Weight matrix descriptions of four eukaryotic RNA polymerase II promoter elements derived from 502 unrelated promoter sequences. J Mol Biol 212:563–578

    Article  CAS  PubMed  Google Scholar 

  • Castro-Rivera E, Samudio I, Safe S (2001) Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements. J Biol Chem 276:30853–30861

    Article  CAS  PubMed  Google Scholar 

  • Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, Lapuk A, Neve RM, Qian Z, Ryder T et al (2006) Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10:529–541

    Article  CAS  PubMed  Google Scholar 

  • Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ (2012) The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature 486:346–352

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dorfman R, Glazer L, Weihe U, Wer NET MF, Shilo BZ (2002) Elbow and Noc define a family of zinc finger proteins controlling morphogenesis of specific tracheal branches. Development 129:3585–3596

    CAS  PubMed  Google Scholar 

  • Duan R, Porter W, Safe S (1998) Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation. Endocrinology 139:1981–1990

    Article  CAS  PubMed  Google Scholar 

  • Dynan WS, Tjian R (1983) The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. Cell 35:79–87

    Article  CAS  PubMed  Google Scholar 

  • Eriksson N, Benton GM, Do CB, Kiefer AK, Mountain JL, Hinds DA, Francke U, Tung JY (2012) Genetic variants associated with breast size also influence breast cancer risk. BMC Med Genet 30(13):53

    Article  Google Scholar 

  • Garcia MJ, Pole JC, Chin SF, Teschendorff A, Naderi A, Ozdag H, Vias M, Kranjac T, Subkhankulova T, Paish C et al (2005) A 1 Mb minimal amplicon at 8p11-12 in breast cancer identifies new candidate oncogenes. Oncogene 24:5235–5245

    Article  CAS  PubMed  Google Scholar 

  • Gerasimova E, Audit B, Roux SG, Khalil A, Gileva O, Argoul F, Naimark O, Arneodo A (2014) Wavelet-based multifractal analysis of dynamic infrared thermograms to assist in early breast cancer diagnosis. Front Physiol 8(5):176

    Google Scholar 

  • Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ (2009) Gastric cancer. Lancet 374:477–490

    Article  PubMed  PubMed Central  Google Scholar 

  • Haverty PM, Fridlyand J, Li L, Getz G, Beroukhim R, Lohr S, Wu TD, Cavet G, Zhang Z, Chant J (2008) High-resolution genomic and expression analyses of copy number alterations in breast tumors. Genes Chromosom Cancer 47:530–542

    Article  CAS  PubMed  Google Scholar 

  • Holland DG, Burleigh A, Git A, Goldgraben MA, Perez-Mancera PA, Chin SF, Hurtado A, Bruna A, Ali HR, Greenwood W et al (2011) ZNF703 is a common luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors inhuman mammary epithelium. EMBO Mol Med 3:167–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosoi Y, Watanabe T, Nakagawa K, Matsumoto Y, Enomoto A, Morita A, Nagawa H, Suzuki N (2004) Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer. Int J Oncol 25:461–468

    CAS  PubMed  Google Scholar 

  • Ji SJ, Periz G, Sockanathan S (2009) Nolz1 is induced by retinoid signals and controls motoneuron subtype identity through distinct repressor activities. Development 136:231–240

    Article  CAS  PubMed  Google Scholar 

  • Kadonaga JT, Courey AJ, Ladika J, Tjian R (1988) Distinct regions of Sp1 modulate DNA binding and transcriptional activation. Science 242:1566–1570

    Article  CAS  PubMed  Google Scholar 

  • Letovsky J, Dynan WS (1989) Measurement of the binding of transcription factor Sp1 to a single GC box recognition sequence. Nucleic Acids Res 17:2639–2653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao X, Deng W, Lu Y, Tao D, Liu Y, Zhang S, Ma Y (2010) Sp1 plays an important role in regulating the transcription of ZNF313. Cell Biol Int 34(9):901–905

    Article  CAS  PubMed  Google Scholar 

  • Ma F, Bi L, Yang G, Zhang M, Liu C, Zhao Y, Wang Y, Wang J, Bai Y, Zhang Y (2014) ZNF703 promotes tumor cell proliferation and invasion and predicts poor prognosis in patients with colorectal cancer. Oncol Rep 32:1071–1077

    Article  CAS  PubMed  Google Scholar 

  • Nakamura M, Runko AP, Sagerström CG (2004) A novel subfamily of zinc finger genes involved in embryonic development. J Cell Biochem 93:887–895

    Article  CAS  PubMed  Google Scholar 

  • Ngwenya S, Safe S (2003) Cell context-dependent differences in the induction of E2F-1 gene expression by 17b-estradiol in MCF-7 and ZR-75 cells. Endocrinology 144:1675–1685

    Article  CAS  PubMed  Google Scholar 

  • Pereira-Castro I, Costa AM, Oliveira MJ, Barbosa I, Rocha AS, Azevedo L, da Costa LT (2013) Characterization of human NLZ1/ZNF703 identifies conserved domains essential for propersubcellular localization and transcriptional repression. J Cell Biochem 114:120–133

    Article  CAS  PubMed  Google Scholar 

  • Philipsen S, Suske G (1999) A tale of three fingers: The family of mammalian Sp/XKLF transcription factors. Nucleic Acids Res 27:2991–3000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reynisdottir I, Arason A, Einarsdottir BO, Gunnarsson H, Staaf J, Vallon-Christersson J, Jonsson G, Ringnér M, Agnarsson BA, Olafsdottir K et al (2013) High expression of ZNF703 independent of amplification indicates worse prognosis in patients with luminal B breast cancer. Cancer Med 2:437–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Runko AP, Sagerstrom CG (2004a) Nlz belongs to a family of zinc-finger-containing repressors and controls segmental gene expression in the zebrafish hindbrain. Dev Biol 262:254–267

    Article  Google Scholar 

  • Runko AP, Sagerstrom CG (2004b) Isolation of nlz2 and characterization of essential domains in Nlz family proteins. J Biol Chem 279:11917–11925

    Article  CAS  PubMed  Google Scholar 

  • Shi Q, Le X, Abbruzzese JL, Peng Z, Qian CN, Tang H, Xiong Q, Wang B, Li XC, Xie K (2001) Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res 61:4143–4154

    CAS  PubMed  Google Scholar 

  • Shi Y, Li J, Liu Y, Ding J, Fan Y, Tian Y, Wang L, Lian Y, Wang K, Shu Y (2015) The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by up regulating ZNF703 expression. Mol Cancer 14:1–13

    Article  Google Scholar 

  • Sircoulomb F, Nicolas N, Ferrari A, Finetti P, Bekhouche I, Rousselet E, Lonigro A, Adélaïde J, Baudelet E, Esteyriès S et al (2011) ZNF703 gene amplification at 8p12 specifies luminal B breast cancer. EMBO Mol Med 3:153–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slorach EM, Chou J, Werb Z (2011) Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization. Genes Dev 25:471–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874

    Article  PubMed  PubMed Central  Google Scholar 

  • Sørlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423

    Article  PubMed  PubMed Central  Google Scholar 

  • Spellman P, Gray J (2011) A new treasure in the breast cancer gene hunt. Nat Med 17:422–423

    Article  CAS  PubMed  Google Scholar 

  • Suske G (1999) The Sp-family of transcription factors. Gene 238:291–300

    Article  CAS  PubMed  Google Scholar 

  • Vyhlidal C, Samudio I, Kladde M, Safe S (2000) Transcriptional activation of transforming growth factor a by estradiol: requirement for both a GC-rich site and an estrogen response element half-site. J Mol Endocrinol 24:329–338

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Dong L, Saville B, Safe S (1999) Transcriptional activation of E2F1 gene expression by 17b-estradiol in MCF-7 cells is regulated by NF-Y-Sp1/estrogen receptor interactions. J Mol Endocrinol 13:1373–1387

    CAS  Google Scholar 

  • Xu W, Zhang S, Qiu W, He G, Liu Y, Sun Y, Ma Y, Dong J, Zhang W (2009) Spermatogenesis-related ring finger ZNF230 promoter: identification and functional analysis. Mol Biol Rep 36:1187–1193

    Article  CAS  PubMed  Google Scholar 

  • Yang G, Ma F, Zhong M, Fang L, Peng Y, Xin X, Zhong J, Yuan F, Gu H, Zhu W et al (2014) ZNF703 acts as an oncogene that promotes progression in gastric cancer. Oncol Rep 31:1877–1882

    Article  CAS  PubMed  Google Scholar 

  • Yao JC, Wang L, Wei D, Gong W, Hassan M, Wu TT, Mansfield P, Ajani J, Xie K (2004) Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clin Cancer Res 10:4109–4117

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Mu X, Huang O, Xie Z, Jiang M, Geng M, Shen K (2013) Luminal breast cancer cell lines overexpressing ZNF703 are resistant to tamoxifen through activation of Akt/mTOR signaling. PLoS ONE 8:e72053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the Department of Medical Genetics of Sichuan University for generously providing plasmids for creating the pGL3-vector, and also for providing the HEK293T cell line.

Funding

This study was funded by the Sichuan Provincial Education Projects [nos. 15ZB0443].

Author contributions

Xiaolin Liao and Sheng He designed the study, Xiaolin Liao and Yongjie Lu conducted the experiments, Junbao Yang, Tao Kuang, Xiaoli Zhou, Bo Jiang, Huiqun Kang and Yanjun Wang analyzed the data, and Xiaolin Liao and Lilin Jiang wrote the manuscript.

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Correspondence to Sheng He.

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Conflict of interest

Xiaolin Liao declares that she has no conflict of interest. Yongjie Lu declares that he has no conflict of interest. Junbao Yang declares that he has no conflict of interest. Tao Kuang declares that she has no conflict of interest. Lilin Jiang declares that she has no conflict of interest. Yanjun Wang declares that she has no conflict of interest. Huiqun Kang declares that she has no conflict of interest. Bo Jiang declares that she has no conflict of interest. Xiaoli Zhou declares that she has no conflict of interest. Sheng He declares that he has no conflict of interest.

Ethical approval

This study was approved by ethics committees of West China Hospital, Sichuan University.

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Written informed consent was obtained from participant.

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Liao, X., Lu, Y., Yang, J. et al. Transcription factor Sp1 is necessary and functional in regulating expression of oncogene ZNF703 . Genes Genom 39, 1107–1115 (2017). https://doi.org/10.1007/s13258-017-0577-9

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  • DOI: https://doi.org/10.1007/s13258-017-0577-9

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