The epithelial splicing regulatorESRP2is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

Wilms tumour (WT), a childhood kidney cancer with embryonal origins, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of fetal kidney with two WT cell lines, using methyl-CpG immunoprecipitation. We filtered our results to remove common cancer-associated epigenetic changes, and to enrich for genes involved in early kidney development. This identified four candidate genes that were hypermethylated in WT cell lines compared to fetal kidney, of whichESRP2(epithelial splicing regulatory protein 2), was the most promising gene for further study.ESRP2was commonly repressed by DNA methylation in WT, and this was shown to occur early in WT development (in nephrogenic rests).ESRP2expression could be reactivated by DNA methyltransferase inhibition in WT cell lines. WhenESRP2was overexpressed in WT cell lines, it acted as an inhibitor of cellular proliferationin vitro,andin vivoit suppressed tumour growth of orthotopic xenografts in nude mice. RNA-seq of the ESRP2-expressing WT cell lines identified several novel splicing targets, in addition to well-characterised targets of ESRP2. We propose a model in which the mesenchymal to epithelial transition that is essential for early kidney development, can be disrupted in to generate WT, either by genetic abnormalities such asWT1mutations, or by epigenetic defects, such asESRP2methylation.