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.

  • Original Article
  • Published:

Transcriptional regulation of KiSS-1 gene expression in metastatic melanoma by specificity protein-1 and its coactivator DRIP-130

Abstract

Loss of the metastasis suppressor gene, KiSS-1 has been strongly correlated to the progression of metastases in numerous types of cancers. The mechanism through which KiSS-1 is lost during metastasis, however, is still not completely known. Previous studies have shown that genetic material on human chromosome 6q16.3–q23 is essential for KiSS-1 expression in normal tissues. Additionally, microcell-mediated transfer of this chromosome in cancerous tissue results in rescued expression of KiSS-1 and reduced metastatic phenotype. Here, we show that loss of Sp1-coactivator protein DRIP-130, which is encoded by human chromosome 6q16.3–q23, results in reduced KiSS-1 promoter activation in highly malignant melanoma cells. Co-expression of Sp1 and DRIP-130 not only rescues KiSS-1 expression, but also induces an inhibition of the invasive and migratory behavior in highly metastatic melanoma cells, similar to the overexpression of KiSS-1 metastasis suppressor gene in those cells. Furthermore, we demonstrate that KiSS-1 expression is regulated by Sp1 elements within the first 100-bp region of the KiSS-1 promoter and that targeted deletion of a single GC-rich region spanning −93 to −58 interrupts Sp1- and DRIP-130-modulated transcriptional control of KiSS-1 expression. Our results thus suggest that DRIP-130 is a key regulator in KiSS-1 transactivation in normal tissue, and that the loss of DRIP-130 expression, as a result of the gross loss of human chromosome 6q16.3–q23, provokes increased tumor metastasis.

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

Access options

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • 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 

  • Banyard J, Anand-Apte B, Symons M, Zetter BR . (2000). Motility and invasion are differentially modulated by Rho family GTPases. Oncogene 19: 580–591.

    Article  CAS  Google Scholar 

  • Black AR, Black JD, Azizkhan-Clifford J . (2001). Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 188: 143–160.

    Article  CAS  Google Scholar 

  • Dong L, Wang W, Wang F, Stoner M, Reed JC, Harigai M et al. (1999). Mechanisms of transcriptional activation of bcl-2 gene expression by 17beta-estradiol in breast cancer cells. J Biol Chem 274: 32099–32107.

    Article  CAS  Google Scholar 

  • Finkenzeller G, Sparacio A, Technau A, Marme D, Siemeister G . (1997). Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression. Oncogene 15: 669–676.

    Article  CAS  Google Scholar 

  • Goldberg SF, Miele ME, Hatta N, Takata M, Paquette-Straub C, Freedman LP et al. (2003). Melanoma metastasis suppression by chromosome 6: evidence for a pathway regulated by CRSP3 and TXNIP. Cancer Res 63: 432–440.

    CAS  PubMed  Google Scholar 

  • Ikeguchi M, Yamaguchi K, Kaibara N . (2004). Clinical significance of the loss of KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in esophageal squamous cell carcinoma. Clin Cancer Res 10: 1379–1383.

    Article  CAS  Google Scholar 

  • Ji C, Casinghino S, McCarthy TL, Centrella M . (1997). Multiple and essential Sp1 binding sites in the promoter for transforming growth factor-beta type I receptor. J Biol Chem 272: 21260–21267.

    Article  CAS  Google Scholar 

  • Jiang Y, Berk M, Singh LS, Tan H, Yin L, Powell CT et al. (2005). KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. Clin Exp Metast 22: 369–376.

    Article  CAS  Google Scholar 

  • Jiang Y, Wang L, Gong W, Wei D, Le X, Yao J et al. (2004). A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer. Clin Exp Metast 21: 755–764.

    Article  CAS  Google Scholar 

  • Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E et al. (2001). The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 276: 34631–34636.

    Article  CAS  Google Scholar 

  • Lania L, Majello B, De Luca P . (1997). Transcriptional regulation by the Sp family proteins. Int J Biochem Cell Biol 29: 1313–1323.

    Article  CAS  Google Scholar 

  • Lee JH, Welch DR . (1997a). Identification of highly expressed genes in metastasis-suppressed chromosome 6/human malignant melanoma hybrid cells using subtractive hybridization and differential display. Int J Cancer 71: 1035–1044.

    Article  CAS  Google Scholar 

  • Lee JH, Welch DR . (1997b). Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res 57: 2384–2387.

    CAS  PubMed  Google Scholar 

  • Liu YN, Lee WW, Wang CY, Chao TH, Chen Y, Chen JH . (2005). Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene 24: 8277–8290.

    Article  CAS  Google Scholar 

  • Masui T, Doi R, Mori T, Toyoda E, Koizumi M, Kami K et al. (2004). Metastin and its variant forms suppress migration of pancreatic cancer cells. Biochem Biophys Res Commun 315: 85–92.

    Article  CAS  Google Scholar 

  • Miele ME, Jewett MD, Goldberg SF, Hyatt DL, Morelli C, Gualandi F et al. (2000). A human melanoma metastasis-suppressor locus maps to 6q16.3–q23. Int J Cancer 86: 524–528.

    Article  CAS  Google Scholar 

  • Mitchell DC, Abdelrahim M, Weng J, Stafford LJ, Safe S, Bar-Eli M et al. (2006). Regulation of KiSS-1 metastasis suppressor gene expression in breast cancer cells by direct interaction of transcription factors activator protein-2alpha and specificity protein-1. J Biol Chem 281: 51–58.

    Article  CAS  Google Scholar 

  • Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A et al. (2001). AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 276: 28969–28975.

    Article  CAS  Google Scholar 

  • Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K et al. (2001). Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 411: 613–617.

    Article  CAS  Google Scholar 

  • Ryu S, Tjian R . (1999). Purification of transcription cofactor complex CRSP. Proc Natl Acad Sci USA 96: 7137–7142.

    Article  CAS  Google Scholar 

  • Ryu S, Zhou S, Ladurner AG, Tjian R . (1999). The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397: 446–450.

    Article  CAS  Google Scholar 

  • Ryuto M, Ono M, Izumi H, Yoshida S, Weich HA, Kohno K et al. (1996). Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. J Biol Chem 271: 28220–28228.

    Article  CAS  Google Scholar 

  • Safe S, Abdelrahim M . (2005). Sp transcription factor family and its role in cancer. Eur J Cancer 41: 2438–2448.

    Article  CAS  Google Scholar 

  • Sanchez-Carbayo M, Capodieci P, Cordon-Cardo C . (2003). Tumor suppressor role of KiSS-1 in bladder cancer: loss of KiSS-1 expression is associated with bladder cancer progression and clinical outcome. Am J Pathol 162: 609–617.

    Article  CAS  Google Scholar 

  • Shi Q, Le X, Abbruzzese JL, Peng Z, Qian CN, Tang H et al. (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 

  • Shirasaki F, Takata M, Hatta N, Takehara K . (2001). Loss of expression of the metastasis suppressor gene KiSS1 during melanoma progression and its association with LOH of chromosome 6q16.3–q23. Cancer Res 61: 7422–7425.

    CAS  PubMed  Google Scholar 

  • Stafford LJ, Xia C, Ma W, Cai Y, Liu M . (2002). Identification and characterization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor. Cancer Res 62: 5399–5404.

    CAS  PubMed  Google Scholar 

  • Steeg PS, Ouatas T, Halverson D, Palmieri D, Salerno M . (2003). Metastasis suppressor genes: basic biology and potential clinical use. Clin Breast Cancer 4: 51–62.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Taatjes DJ, Tjian R . (2004). Structure and function of CRSP/Med2; a promoter-selective transcriptional coactivator complex. Mol Cell 14: 675–683.

    Article  CAS  Google Scholar 

  • Tellez C, McCarty M, Ruiz M, Bar-Eli M . (2003). Loss of activator protein-2alpha results in overexpression of protease-activated receptor-1 and correlates with the malignant phenotype of human melanoma. J Biol Chem 278: 46632–46642.

    Article  CAS  Google Scholar 

  • Wang J, Bannon MJ . (2005). Sp1 and Sp3 activate transcription of the human dopamine transporter gene. J Neurochem 93: 474–482.

    Article  CAS  Google Scholar 

  • Wang L, Wei D, Huang S, Peng Z, Le X, Wu TT et al. (2003). Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res 9: 6371–6380.

    CAS  PubMed  Google Scholar 

  • Yao JC, Wang L, Wei D, Gong W, Hassan M, Wu TT et al. (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 (Part 1): 4109–4117.

    Article  CAS  Google Scholar 

  • Zhu GH, Lenzi M, Schwartz EL . (2002). The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells. Oncogene 21: 8477–8485.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work is partially supported by a Predoctoral Traineeship Awards (W81XWH-05-1-0353 and DAMD17-03-1-0435) from DOD Breast Cancer Program to DM and LS, and by the NIH grants (5R01HL064792 and 1R01CA106479) to ML. We thank Dr Jun Qin at Baylor College of Medicine for the DRIP-130 construct.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mitchell, D., Stafford, L., Li, D. et al. Transcriptional regulation of KiSS-1 gene expression in metastatic melanoma by specificity protein-1 and its coactivator DRIP-130. Oncogene 26, 1739–1747 (2007). https://doi.org/10.1038/sj.onc.1209963

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209963

Keywords

This article is cited by

Search

Quick links