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Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance

Author

Listed:
  • Malin Wickström

    (Childhood Cancer Research Unit, Karolinska Institutet)

  • Cecilia Dyberg

    (Childhood Cancer Research Unit, Karolinska Institutet)

  • Jelena Milosevic

    (Childhood Cancer Research Unit, Karolinska Institutet)

  • Christer Einvik

    (University Hospital of North Norway)

  • Raul Calero

    (Childhood Cancer Research Unit, Karolinska Institutet)

  • Baldur Sveinbjörnsson

    (Childhood Cancer Research Unit, Karolinska Institutet
    University of Tromsø)

  • Emma Sandén

    (Glioma Immunotherapy Group, Lund University)

  • Anna Darabi

    (Glioma Immunotherapy Group, Lund University)

  • Peter Siesjö

    (Glioma Immunotherapy Group, Lund University)

  • Marcel Kool

    (German Cancer Research Center, DKFZ)

  • Per Kogner

    (Childhood Cancer Research Unit, Karolinska Institutet)

  • Ninib Baryawno

    (Harvard University
    Center for Regenerative Medicine and the Cancer Center, Massachusetts General Hospital
    Harvard Stem Cell Institute)

  • John Inge Johnsen

    (Childhood Cancer Research Unit, Karolinska Institutet)

Abstract

The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is commonly overexpressed in cancers and is implicated in the development of chemoresistance. The use of drugs inhibiting MGMT has been hindered by their haematologic toxicity and inefficiency. As a different strategy to inhibit MGMT we investigated cellular regulators of MGMT expression in multiple cancers. Here we show a significant correlation between Wnt signalling and MGMT expression in cancers with different origin and confirm the findings by bioinformatic analysis and immunofluorescence. We demonstrate Wnt-dependent MGMT gene expression and cellular co-localization between active β-catenin and MGMT. Pharmacological or genetic inhibition of Wnt activity downregulates MGMT expression and restores chemosensitivity of DNA-alkylating drugs in mouse models. These findings have potential therapeutic implications for chemoresistant cancers, especially of brain tumours where the use of temozolomide is frequently used in treatment.

Suggested Citation

  • Malin Wickström & Cecilia Dyberg & Jelena Milosevic & Christer Einvik & Raul Calero & Baldur Sveinbjörnsson & Emma Sandén & Anna Darabi & Peter Siesjö & Marcel Kool & Per Kogner & Ninib Baryawno & Joh, 2015. "Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9904
    DOI: 10.1038/ncomms9904
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