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, John Inge Johnsen

Research output: Contribution to journalArticlepeer-review

170 Citations (Scopus)

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.

Original languageEnglish
Article number8904
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 25 Nov 2015
Externally publishedYes

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