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:

Genetic and epigenetic alterations of the APC gene in malignant melanoma

Oncogene volume 23, pages 5215–5226 (2004)Cite this article

Abstract

High levels of β-catenin and activating mutations in the β-catenin gene (CTNNB1) have been demonstrated in malignant melanomas, implicating dysregulated Wnt signalling in the pathogenesis of this malignancy. We systematically examined melanoma cell lines for activating CTNNB1 mutations as well as genetic and epigenetic alterations of the adenomatous polyposis coli gene (APC), another key component of the Wnt signalling transduction pathway. Of 40 cell lines tested, one carried a truncating APC mutation and loss of the corresponding wild-type allele, and one carried a CTNNB1 missense mutation. Hypermethylation of APC promoter 1A was present in five of the cell lines (13%) and in nine of 54 melanoma biopsies (17%). Cells with truncating APC or activating CTNNB1 mutations showed increased transcription from endogenous and ectopic β-catenin/T-cell factor (Tcf)-responsive target genes, consistent with the known effects of these alterations on β-catenin stability and Tcf transactivation. In contrast, cell lines with APC promoter 1A hypermethylation did not show increased Wnt signalling, probably due to residual APC activity expressed from promoter 1B. Suppression of APC transcripts in melanoma cells by stable expression of short hairpin RNAs led to a Wnt signalling-independent increase in cell proliferation, but also reduced the invasive growth in collagen type I. Collectively, our data suggest that the tumour-suppressive function of APC in melanocytic cells is dose dependent. We propose that epigenetic silencing of promoter 1A may contribute to the development of malignant melanoma by reducing the expression of APC to a level that promotes cell proliferation without compromising the invasive capacity.

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
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Baeg GH, Matsumine A, Kuroda T, Bhattacharjee RN, Miyashiro I, Toyoshima K and Akiyama T . (1995). EMBO J., 14, 5618–5625.

  • Brummelkamp TR, Bernards R and Agami R . (2002). Science, 296, 550–553.

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

  • Carmen AA, Griffin PR, Calaycay JR, Rundlett SE, Suka Y and Grunstein M . (1999). Proc. Natl. Acad. Sci. USA, 96, 12356–12361.

  • Chen C, Yang MC and Yang TP . (2001). J. Biol. Chem., 276, 320–328.

  • Coffee B, Zhang F, Warren ST and Reines D . (1999). Nat. Genet., 22, 98–101.

  • Cremonesi L, Firpo S, Ferrari M, Righetti PG and Gelfi C . (1997). Biotechniques, 22, 326–330.

  • Demunter A, Libbrecht L, Degreef H, Wolf-Peeters C and van den Oord JJ . (2002). Mod. Pathol., 15, 454–461.

  • Esteller M, Sparks A, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Gonzalez S, Tarafa G, Sidransky D, Meltzer SJ, Baylin SB and Herman JG . (2000). Cancer Res., 60, 4366–4371.

  • Etienne-Manneville S and Hall A . (2003). Nature, 421, 753–756.

  • Fodde R . (2002). Eur. J. Cancer, 38, 867–871.

  • Fodde R . (2003). Nat. Cell Biol., 5, 190–192.

  • Fodde R, Smits R and Clevers H . (2001). Nat. Rev. Cancer, 1, 55–67.

  • Furuuchi K, Tada M, Yamada H, Kataoka A, Furuuchi N, Hamada J, Takahashi M, Todo S and Moriuchi T . (2000). Am. J. Pathol., 156, 1997–2005.

  • Giles RH, van Es JH and Clevers H . (2003). Biochim. Biophys. Acta, 1653, 1–24.

  • Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF and Zeuthen J . (1997). Cancer Res., 57, 3660–3663.

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B and Kinzler KW . (1998). Science, 281, 1509–1512.

  • Hiltunen MO, Alhonen L, Koistinaho J, Myohanen S, Paakkonen M, Marin S, Kosma VM and Janne J . (1997). Int. J. Cancer, 70, 644–648.

  • Horii A, Nakatsuru S, Miyoshi Y, Ichii S, Nagase H, Ando H, Yanagisawa A, Tsuchiya E, Kato Y and Nakamura Y . (1992a). Cancer Res., 52, 6696–6698.

  • Horii A, Nakatsuru S, Miyoshi Y, Ichii S, Nagase H, Kato Y, Yanagisawa A and Nakamura Y . (1992b). Cancer Res., 52, 3231–3233.

  • Ishidate T, Matsumine A, Toyoshima K and Akiyama T . (2000). Oncogene, 19, 365–372.

  • Jho EH, Zhang T, Domon C, Joo CK, Freund JN and Costantini F . (2002). Mol. Cell. Biol., 22, 1172–1183.

  • Kawakami K, Brabender J, Lord RV, Groshen S, Greenwald BD, Krasna MJ, Yin J, Fleisher AS, Abraham JM, Beer DG, Sidransky D, Huss HT, Demeester TR, Eads C, Laird PW, Ilson DH, Kelsen DP, Harpole D, Moore MB, Danenberg KD, Danenberg PV and Meltzer SJ . (2000). J. Natl. Cancer Inst., 92, 1805–1811.

  • Kielman MF, Rindapaa M, Gaspar C, van Poppel N, Breukel C, van Leeuwen S, Taketo MM, Roberts S, Smits R and Fodde R . (2002). Nat. Genet., 32, 594–605.

  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B and Clevers H . (1997). Science, 275, 1784–1787.

  • Lerman LS and Silverstein K . (1987). Methods Enzymol., 155, 482–501.

  • Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, Cho KR and Fearon ER . (2002). J. Biol. Chem., 277, 21657–21665.

  • Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de WM, Clevers H, Schlag PM, Birchmeier W and Behrens J . (2002). Mol. Cell. Biol., 22, 1184–1193.

  • Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T and Nakamura Y . (1998). Cancer Res., 58, 2524–2527.

  • Mogensen MM, Tucker JB, Mackie JB, Prescott AR and Nathke IS . (2002). J. Cell Biol., 157, 1041–1048.

  • Moreno-Bueno G, Hardisson D, Sanchez C, Sarrio D, Cassia R, Garcia-Rostan G, Prat J, Guo M, Herman JG, Matias-Guiu X, Esteller M and Palacios J . (2002). Oncogene, 21, 7981–7990.

  • Oda H, Imai Y, Nakatsuru Y, Hata J and Ishikawa T . (1996). Cancer Res., 56, 3320–3323.

  • Omholt K, Platz A, Ringborg U and Hansson J . (2001). Int. J. Cancer, 92, 839–842.

  • Pollock PM and Hayward N . (2002). Melanoma Res., 12, 183–186.

  • Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T, Ruzicka T and Reifenberger G . (2002). Int. J. Cancer, 100, 549–556.

  • Rimm DL, Caca K, Hu G, Harrison FB and Fearon ER . (1999). Am. J. Pathol., 154, 325–329.

  • Rubinfeld B, Robbins P, El Gamil M, Albert I, Porfiri E and Polakis P . (1997). Science, 275, 1790–1792.

  • Tetsu O and McCormick F . (1999). Nature, 398, 422–426.

  • Tsuchiya T, Tamura G, Sato K, Endoh Y, Sakata K, Jin Z, Motoyama T, Usuba O, Kimura W, Nishizuka S, Wilson KT, James SP, Yin J, Fleisher AS, Zou T, Silverberg SG, Kong D and Meltzer SJ . (2000). Oncogene, 19, 3642–3646.

  • Usadel H, Brabender J, Danenberg KD, Jeronimo C, Harden S, Engles J, Danenberg PV, Yang S and Sidransky D . (2002). Cancer Res., 62, 371–375.

  • Virmani AK, Rathi A, Sathyanarayana UG, Padar A, Huang CX, Cunnigham HT, Farinas AJ, Milchgrub S, Euhus DM, Gilcrease M, Herman J, Minna JD and Gazdar AF . (2001). Clin. Cancer Res., 7, 1998–2004.

  • Worm J, Aggerholm A and Guldberg P . (2001a). Clin. Chem., 47, 1183–1189.

  • Worm J, Kirkin AF, Dzhandzhugazyan KN and Guldberg P . (2001b). J. Biol. Chem., 276, 39990–40000.

  • Wu R, Zhai Y, Fearon ER and Cho KR . (2001). Cancer Res., 61, 8247–8255.

  • Xiao H, Hasegawa T and Isobe K . (1999). J. Cell. Biochem., 73, 291–302.

  • Yan D, Wiesmann M, Rohan M, Chan V, Jefferson AB, Guo L, Sakamoto D, Caothien RH, Fuller JH, Reinhard C, Garcia PD, Randazzo FM, Escobedo J, Fantl WJ and Williams LT . (2001). Proc. Natl. Acad. Sci. USA, 98, 14973–14978.

  • Zeki K, Spambalg D, Sharifi N, Gonsky R and Fagin JA . (1994). J. Clin. Endocrinol. Metab., 79, 1317–1321.

  • Zumbrunn J, Kinoshita K, Hyman AA and Nathke IS . (2001). Curr. Biol., 11, 44–49.

Download references

Acknowledgements

We thank Tina Seremet and Vibeke Ahrenkiel for expert technical assistance and Dr Reuven Agami for kindly providing the pSUPER plasmid. This study was supported by grants from the Danish Cancer Society, the Neye Foundation, the Danish Medical Research Council, the Danish Cancer Research Foundation, the Kaarsen Foundation, and the Novo Nordisk Foundation.

Author information

Authors and Affiliations

  1. Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, DK-2100, Denmark

    Jesper Worm, Claus Christensen, Kirsten Grønbæk & Per Guldberg

  2. Department of Cancer Studies and Molecular Medicine, Robert Kilpatrick Clinical Sciences Building, University of Leicester, UK

    Eugene Tulchinsky

Authors
  1. Jesper Worm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claus Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kirsten Grønbæk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eugene Tulchinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Per Guldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Per Guldberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Worm, J., Christensen, C., Grønbæk, K. et al. Genetic and epigenetic alterations of the APC gene in malignant melanoma. Oncogene 23, 5215–5226 (2004). https://doi.org/10.1038/sj.onc.1207647

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207647

Keywords

This article is cited by

Search

Advanced search

Quick links