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 Paper
  • Published:

CpG methylation in the Fhit regulatory region: relation to Fhit expression in murine tumors

Oncogene volume 23, pages 3990–3998 (2004)Cite this article

Abstract

To determine if: (1) 5′ CpG island methylation is related to Fhit inactivation; (2) there are tumor or carcinogen-specific methylation patterns, we examined 35 CpG sites in the promoter, exon and intron 1 of the mouse Fhit gene. In primary tumors of lung, urinary bladder and tongue, induced by different carcinogens, 15–35% of sites were methylated, with specific methylation patterns associated with each cancer type, suggesting cancer- or tissue-specific methylation patterns. The methylation patterns were associated with reduced Fhit expression, as determined by immunohistochemical analyses. Methylation of rat Fhit 5′ CpGs in mammary adenocarcinomas, detected by methylation specific PCR amplification, also correlated with reduced gene expression. Thus, there was an overall association between promoter/exon 1 methylation and decreased Fhit expression. In contrast, in cancer-derived cell lines 70–95% of the CpG sites were methylated. This is the first detailed study of the relationship between Fhit 5′ CpG island methylation and Fhit expression in murine tumors, our main models for preclinical cancer studies, and provides evidence that loss of Fhit expression and methylation are correlated in these mouse models and these models will be useful to examine the complex relationships among gene expression, methylation patterns and organ specificity.

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
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, Fullwood P, Chauhan A, Waler R, Shaw JA, Hosoe S, Lerman MI, Minna JD, Maher ER and Latif F . (2001). Oncogene, 20, 1509–1518.

  • Baffa R, Gomella LG, Vecchione A, Bassi P, Sedor J, Calviello CM, Gardiman M, Minimo C, Strup SE, McCue PA, Kovatich A, Pagano F, Huebner K and Croce CM . (2000). Am. J. Pathol., 156, 419–424.

  • Baylin SB, Hoppener JW, de Bustros A, Steenbergh PH, Lips CJ and Nelkin BD . (1986). Cancer Res., 46, 2917–2922.

  • Cameron EE, Bachman KE, Myohanen S, Herman JG and Baylin SB . (1999). Nat. Genet., 21, 103–107.

  • Clark SJ and Melki J . (2002). Oncogene, 21, 5380–5387.

  • Druck T, Berk L and Huebner K . (1998). Oncol. Res., 10, 341–345.

  • Druck T, Hadaczek P, Fu TB, Ohta M, Siprashvilli Z, Baffa R, Negrini M, Kastury K, Veronese ML, Rosen D, Rothstein J, McCue P, Cotticelli MG, Inoue H, Croce CM and Huebner K . (1997). Cancer Res., 57, 504–512.

  • Dumon KR, Ishii H, Fong LY, Zanesi N, Fidanza V, Mancini R, Vecchione A, Baffa R, Trapasso F, During MJ, Huebner K and Croce CM . (2001). Proc. Natl. Acad. Sci. USA, 98, 3346–3351.

  • Esteller M, Corn PG, Baylin SB and Herman JG . (2001). Cancer Res., 61, 3225–3229.

  • Fong LYY, Fidanza V, Zanesi N, Lock L, Siracusa L, Mancini R, Siprashvili Z, Ottery M, Martin SE, Druck T, McCue PA, Croce CM and Huebner K . (2000). Proc. Natl. Acad. Sci. USA, 97, 4742–4747.

  • Glover TW, Hoge A, Miller DE, Ascara-Wilke JE, Adam A, Dagenais SL, Wilke CM, Dierick HA and Beer DG . (1998). Cancer Res., 58, 3409–3414.

  • Gonzalgo ML, Hayashida T, Bender CM, Pao MM, Tsai YC, Gonzales FA, Nguyen HD, Nguyen TT and Jones PA . (1998). Cancer Res., 58, 1245–1252.

  • Grubbs CJ, Lubet RA, Koki AT, Leahy KM, Masferrer JL, Steele VE, Kelloff GJ, Hill DL and Seibert K . (2000). Cancer Res., 60, 5999–6002.

  • Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9821–9826.

  • Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DSR, Gnarra JR, Linehan WM and Baylin SB . (1994). Proc. Natl. Acad. Sci. USA, 91, 9700–9704.

  • Huebner K and Croce CM . (2001). Nat. Rev. Cancer, 1, 214–221.

  • Ingvarsson S, Agnarsson BA, Sigbjornsdottir BI, Kallioniemi OP, Barkardottir RB, Kovatich A, Schwarting R, Hauck WW, Huebner K and McCue PA . (1999). Cancer Res., 59, 2682–2689.

  • Kolomietz E, Marrano P, Yee K, Thai B, Braude I, Kolomietz A, Chun K, Minkin S, Kamel-Reid S, Minden M and Squire JA . (2003). Leukemia, 17, 1313–1323.

  • Lubet RA, Fong LY, Huebner K, Altieri DC, Steele VE, Kopelovich L, Kavanaugh C, Juliana MM and Grubbs CJ . (2003). Carcinogenesis (submitted).

  • Maruyama R, Toyooka S, Toyooka KO, Harada K, Virmani AK, Zochbauer-Muller S, Farinas AJ, Vakar-Lopez F, Minna JD, Sagalowsky A, Czerniak B and Gazdar AF . (2001). Cancer Res., 61, 8659–8663.

  • Nigro JM, Takahashi MA, Ginzinger DG, Law M, Passe S, Jenkins RB and Aldape K . (2001). Am. J. Pathol., 158, 1253–1262.

  • Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM and Huebner K . (1996). Cell, 84, 587–597.

  • Paz MF, Fraga MF, Avila S, Guo M, Pollan M, Herman JG and Esteller M . (2003). Cancer Res., 63, 1114–1121.

  • Pekarsky Y, Druck T, Cotticelli MG, Ohta M, Shou J, Mendrola J, Montgomery JC, Buchberg AM, Siracusa LD, Manenti G, Fong LY, Dragani TA, Croce CM and Huebner K . (1998). Cancer Res., 58, 3401–3408.

  • Skopelitou AS, Gloustianou G, Bai M and Huebner K . (2001). In vivo, 15, 169–173.

  • Soejima K, Fang W and Rollins BJ . (2003). Oncogene, 22, 4723–4733.

  • Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, Inoue H, Tornielli S, Pilotti S, De Gregorio L, Pastorino U, Pierotti MA, Ohta M, Huebner K and Croce CM . (1996). Cell, 85, 17–26.

  • Sozzi G, Pastorino U, Moiraghi L, Tagliabue E, Pezzella F, Ghirelli C, Tornielli S, Sard L, Huebner K, Pierotti MA, Croce CM and Pilotti S . (1998). Cancer Res., 58, 5032–5037.

  • Sutherland JE, Peng W, Zhang Q and Costa M . (2001). Mutat Res., 479, 225–233.

  • Tanaka H, Shimada Y, Harada H, Shinoda M, Hatooka S, Imamura M and Ishizaki K . (1998). Cancer Res., 58, 3429–3434.

  • Wary K, Lou Z, Buchberg A, Siracusa L, Druck T, LaForgia S and Huebner K . (1993). Cancer Res., 53, 1498–1502.

  • Zanesi N, Fidanza V, Fong LY, Mancini R, Druck T, Valtieri M, Rudiger T, McCue PA, Croce CM and Huebner K . (2001). Proc. Natl. Acad. Sci. USA, 98, 10250–10255.

  • Zochbauer-Muller S, Fong KM, Maitra A, lam S, Goradts J, Ashfuq R, Virmani Ak, Milchgrub S, Gazdar AF and Minna JD . (2001). Cancer Res., 61, 3581–3585.

Download references

Acknowledgements

This research was supported by National Cancer Institute Contract N01-CN-15128, N01-CN-15113, N01-CN-25007, a subaward from Ohio Medical College, as well as grants CA77738 and CA56036 from the National Cancer Institute. Gulnur Guler was supported by funding from the University of Hacettepe and from the National Institutes of Health.

Author information

Author notes

  1. Shuang-Yin Han and Dimitrios Iliopoulos: These authors contributed equally to this work

Authors and Affiliations

  1. Kimmel Cancer Center, Thomas Jefferson University, 1008 BLSB, 233S. 10th Street, Philadelphia, 19107, PA, USA

    Shuang-Yin Han, Dimitrios Iliopoulos, Teresa Druck, Gulnur Guler, Louise YY Fong & Kay Huebner

  2. Department of Surgery, University of Alabama at Birmingham, Birmingham, 35294, AL, USA

    Clinton J Grubbs

  3. Department of Pathology, Medical College of Ohio, Toledo, OH, USA

    Michael Pereira

  4. Department of Surgery, Washington University, St Louis, MO, USA

    Zhongqiu Zhang & Ming You

  5. Division of Cancer Prevention and Control, DCPC, National Cancer Institute, Bethesda, 20852, MD, USA

    Ronald A Lubet

  6. Department of Pathology, Hacettepe University, Ankara, Turkey

    Gulnur Guler

Authors
  1. Shuang-Yin Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dimitrios Iliopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teresa Druck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gulnur Guler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Clinton J Grubbs
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhongqiu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ming You
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ronald A Lubet
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Louise YY Fong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kay Huebner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kay Huebner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Han, SY., Iliopoulos, D., Druck, T. et al. CpG methylation in the Fhit regulatory region: relation to Fhit expression in murine tumors. Oncogene 23, 3990–3998 (2004). https://doi.org/10.1038/sj.onc.1207526

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207526

Keywords

This article is cited by

Search

Advanced search

Quick links