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.

  • Letter
  • Published:

A variable number of tandem repeats polymorphism in an E2F-1 binding element in the 5′ flanking region of SMYD3 is a risk factor for human cancers

Nature Genetics volume 37, pages 1104–1107 (2005)Cite this article

Abstract

Histone modification is a crucial step in transcriptional regulation, and deregulation of the modification process is important in human carcinogenesis. We previously reported that upregulation of SMYD3, a histone methyltransferase, promoted cell growth in human colorectal and hepatocellular carcinomas. Here we report significant associations between homozygosity with respect to an allele with three tandem repeats of a CCGCC unit in the regulatory region of SMYD3 and increased risk of colorectal cancer (P = 9.1 × 10−6, odds ratio = 2.58), hepatocellular carcinoma (P = 2.3 × 10−8, odds ratio = 3.50) and breast cancer (P = 7.0 × 10−10, odds ratio = 4.48). This tandem-repeat sequence is a binding site for the transcriptional factor E2F-1. In a reporter assay, plasmids containing three repeats of the binding motif (corresponding to the high-risk allele) had higher activity than plasmids containing two repeats (the low-risk allele). These data suggest that the common variable number of tandem repeats polymorphism in SMYD3 is a susceptibility factor for some types of human cancer.

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: Identification of putative E2F-1–binding sequences in the SMYD3 promoter region and involvement of E2F-1 in the induction of SMYD3.
Figure 2: Accumulation of SMYD3 protein after association of E2F-1 with the putative E2F-1–binding sequences.
Figure 3: Association between activity of the SMYD3 promoter and a polymorphism in the promoter region.

Similar content being viewed by others

Accession codes

Accessions

BINDPlus

References

  1. Hamamoto, R. et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat. Cell Biol. 6, 731–740 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Boggs, B.A. et al. Differentially methylated forms of histone H3 show unique association patterns with inactive human X chromosomes. Nat. Genet. 30, 73–76 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Litt, M.D., Simpson, M., Gaszner, M., Allis, C.D. & Felsenfeld, G. Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus. Science 293, 2453–2455 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Schneider, R. et al. Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nat. Cell Biol. 6, 73–77 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Bernstein, B.E. et al. Methylation of histone H3 Lys 4 in coding regions of active genes. Proc. Natl. Acad. Sci. USA 99, 8695–8700 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bell, L.A. & Ryan, K.M. Life and death decisions by E2F–1. Cell Death Differ. 11, 137–142 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Black, A.R. & Azizkhan-Clifford, J. Regulation of E2F: a family of transcription factors involved in proliferation control. Gene 237, 281–302 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Stevaux, O. & Dyson, N.J. A revised picture of the E2F transcriptional network and RB function. Curr. Opin. Cell Biol. 14, 684–691 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Phillips, A.C. & Vousden, K.H. E2F–1 induced apoptosis. Apoptosis 6, 173–182 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Dyson, N. The regulation of E2F by pRB-family proteins. Genes Dev. 12, 2245–2262 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Harbour, J.W. & Dean, D.C. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 14, 2393–2409 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Spire-Vayron de la Moureyre, C. et al. Characterization of a variable number tandem repeat region in the thiopurine S-methyltransferase gene promoter. Pharmacogenetics 9, 189–198 (1999).

    CAS  PubMed  Google Scholar 

  13. Nakamura, Y., Carlson, M., Krapcho, K., Kanamori, M. & White, R. New approach for isolation of VNTR markers. Am. J. Hum. Genet. 43, 854–859 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nakamura, Y., Koyama, K. & Matsushima, M. VNTR (variable number of tandem repeat) sequences as transcriptional, translational, or functional regulators. J. Hum. Genet. 43, 149–152 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Nakamura, Y. et al. Variable number of tandem repeat (VNTR) markers for human gene mapping. Science 235, 1616–1622 (1987).

    Article  CAS  PubMed  Google Scholar 

  16. Zehbe, I., Voglino, G., Wilander, E., Genta, F. & Tommasino, M. Codon 72 polymorphism of p53 and its association with cervical cancer. Lancet 354, 218–219 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Bond, G.L. et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591–602 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Cai, Q. et al. Association of breast cancer risk with a GT dinucleotide repeat polymorphism upstream of the estrogen receptor-alpha gene. Cancer Res. 63, 5727–5730 (2003).

    CAS  PubMed  Google Scholar 

  19. Krippl, P. et al. The 5A/6A polymorphism of the matrix metalloproteinase 3 gene promoter and breast cancer. Clin. Cancer Res. 10, 3518–3520 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. De Vivo, I., Hankinson, S.E., Colditz, G.A. & Hunter, D.J. A functional polymorphism in the progesterone receptor gene is associated with an increase in breast cancer risk. Cancer Res. 63, 5236–5238 (2003).

    CAS  PubMed  Google Scholar 

  21. Okabe, H. et al. Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1. Cancer Res. 63, 3043–3048 (2003).

    CAS  PubMed  Google Scholar 

  22. Tang, C.J., Chuang, C.K., Hu, H.M. & Tang, T.K. The zinc finger domain of Tzfp binds to the tbs motif located at the upstream flanking region of the Aie1 (aurora-C) kinase gene. J. Biol. Chem. 276, 19631–19639 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Y. Yamane for technical assistance and M. Kubo, K. Yamazaki, M. Kunizaki, K. Obama, M. Sakai, T. Kobayashi, K. Ura and S. Matsushima for discussions. This work was supported in part by a Research for the Future Program Grant from the Japan Society for the Promotion of Science.

Author information

Author notes

  1. Masataka Tsuge and Ryuji Hamamoto: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Masataka Tsuge, Ryuji Hamamoto, Fabio Pittella Silva & Yusuke Nakamura

  2. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Masataka Tsuge & Kazuaki Chayama

  3. Laboratory for SNP Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Yozo Ohnishi

  4. Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan

    Naoyuki Kamatani

  5. Promotion of Genome-based Medicine Project, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Yoichi Furukawa

Authors
  1. Masataka Tsuge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryuji Hamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fabio Pittella Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yozo Ohnishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazuaki Chayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoyuki Kamatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoichi Furukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yusuke Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yusuke Nakamura.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Sequences of oligonucleotides. (PDF 21 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsuge, M., Hamamoto, R., Silva, F. et al. A variable number of tandem repeats polymorphism in an E2F-1 binding element in the 5′ flanking region of SMYD3 is a risk factor for human cancers. Nat Genet 37, 1104–1107 (2005). https://doi.org/10.1038/ng1638

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1638

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing