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

M. Wickström,Cecilia Dyberg,J. Milosevic,C. Einvik,Raul Calero,B. Sveinbjörnsson,Emma Sandén,A. Darabi,P. Siesjö,M. Kool,P. Kogner,N. Baryawno,J. Johnsen

Published 2015 in Nature Communications

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. The high expression of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) often confers resistance to chemotherapy in several cancers. In this study, the authors propose the inhibition of the Wnt signalling pathway as an alternative strategy to modulate MGMT expression and sensitize tumours to chemotherapy.

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