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

摘要

The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is commonlyoverexpressed in cancers and is implicated in the development of chemoresistance. The useof drugs inhibiting MGMT has been hindered by their haematologic toxicity and inefficiency.As a different strategy to inhibit MGMT we investigated cellular regulators of MGMTexpression in multiple cancers. Here we show a significant correlation between Wnt signallingand MGMT expression in cancers with different origin and confirm the findings by bioinformaticanalysis and immunofluorescence. We demonstrate Wnt-dependent MGMT geneexpression and cellular co-localization between active β-catenin and MGMT. Pharmacologicalor genetic inhibition of Wnt activity downregulates MGMT expression and restoreschemosensitivity of DNA-alkylating drugs in mouse models. These findings have potentialtherapeutic implications for chemoresistant cancers, especially of brain tumours where theuse of temozolomide is frequently used in treatment.