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

Malin Wickström, Cecilia Dyberg, Jelena Milosevic, Christer Einvik, Raul Calero, Baldur Sveinbjörnsson, Emma Sandén, Anna Darabi, Peter Siesjö, Marcel Kool, Per Kogner, Ninib Baryawno () and John Inge Johnsen ()
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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
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
John Inge Johnsen: Childhood Cancer Research Unit, Karolinska Institutet

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9904

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