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The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways

Oncogene volume 28, pages 1506–1517 (2009)Cite this article

Abstract

The Tip60 histone acetyltransferase belongs to a multimolecular complex that contains many chromatin remodeling enzymes including the ATPase p400, a protein involved in nucleosomal incorporation of specific histone variants and that can directly or indirectly repress some Tip60-dependent pathways. Tip60 activity is critical for the cellular response to DNA damage and is affected during cancer progression. Here, we found that the ratio between Tip60 and p400 mRNAs is affected in most colorectal carcinoma. Strikingly, reversing the p400/Tip60 imbalance by Tip60 overexpression or the use of siRNAs resulted in increased apoptosis and decreased proliferation of colon-cancer-derived cells, suggesting that this ratio defect is important for cancer progression. Furthermore, we demonstrate that the p400/Tip60 ratio controls the oncogene-induced DNA damage response, a known anticancer barrier. Finally, we found that it is also critical for the response to 5-fluorouracil, a first-line treatment against colon cancer. Together, our data indicate that the p400/Tip60 ratio is critical for colon cancer cells proliferation and response to therapeutic drugs through the control of stress–response pathways.

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Acknowledgements

We thank Professor JF Beaulieu and K Helin for materials, Professor B Ducommun, Dr G Legube and Dr Y Canitrot for critical reading of the paper. We also acknowledge JJ Maoret, responsible person of the QPCR platform at IFR31 (INSERM), as well as S Mazeres (IPBS) and P Grosclaude (INSERM) for their help to format the data concerning tumor analysis. This work was supported by a grant to DT as a ‘subvention libre’ from the ARC and the Institut National du Cancer (INCa), Cancéropôle Grand Sud-Ouest (ACI 2004/2007, to CC). LM and ST were supported by studentships from the French Ministry of Science and the ARC, respectively, whereas FE was supported by a fellowship from the ‘Fondation de France’.

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Author notes

  1. L Mattera, F Escaffit, M Chevillard-Briet and C Cazaux: These authors contributed equally to this work.

Authors and Affiliations

  1. LBCMCP, CNRS, Toulouse, France

    L Mattera, F Escaffit, S Tyteca, M Chevillard-Briet & D Trouche

  2. Université de Toulouse, UPS, Toulouse, France

    L Mattera, F Escaffit, M-J Pillaire, J Selves, S Tyteca, J-S Hoffmann, P-A Gourraud, M Chevillard-Briet, C Cazaux & D Trouche

  3. IPBS, CNRS, Toulouse, France

    M-J Pillaire, J-S Hoffmann & C Cazaux

  4. CPTP, INSERM, Toulouse, France

    J Selves

  5. Service d'Epidémiologie, Hôpitaux de Toulouse, INSERM, Toulouse, France

    P-A Gourraud

Authors
  1. L Mattera
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  2. F Escaffit
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  5. S Tyteca
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  8. M Chevillard-Briet
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  9. C Cazaux
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  10. D Trouche
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Corresponding author

Correspondence to D Trouche.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Mattera, L., Escaffit, F., Pillaire, MJ. et al. The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways. Oncogene 28, 1506–1517 (2009). https://doi.org/10.1038/onc.2008.499

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  • DOI: https://doi.org/10.1038/onc.2008.499

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