The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

Danny N Legge, Whei F Moriarty, David A Lee, Marianna Szemes, Asef Zahed, Leonidas Panousopoulos, Wan Yun Chung, Yara Aghabi, Jasmin Barratt, Richard Williams, Kathy Pritchard-Jones, Karim T A Malik, Sebastian Oltean*, Keith W Brown*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Wilms tumour (WT), an embryonal kidney cancer, 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 foetal kidney with two WT cell lines, filtering our results to remove common cancer-associated epigenetic changes and to enrich for genes involved in early kidney development. This identified four hypermethylated genes, of which ESRP2 (epithelial splicing regulatory protein 2) was the most promising for further study. ESRP2 was commonly repressed by DNA methylation in WT, and this occurred early in WT development (in nephrogenic rests). ESRP2 expression was reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was overexpressed in WT cell lines, it inhibited cellular proliferation in vitro, and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA-seq of the ESRP2-expressing WT cell lines identified several novel splicing targets. We propose a model in which epigenetic inactivation of ESRP2 disrupts the mesenchymal to epithelial transition in early kidney development to generate WT.
Original languageEnglish
Number of pages18
JournalMolecular Oncology
Early online date14 Sep 2021
DOIs
Publication statusPublished - 28 Sep 2021

Bibliographical note

Funding Information:
The authors thank Professor Herman Yeger (University of Toronto) for the gift of the Wit49 cell line; Prof Russ Carstens (University of Pennsylvania) for the plasmids; Dr Madhu Kollareddy for the STR profile of Wit49; the Bristol Genetics Laboratory, Southmead Hospital, for help with pyrosequencing; Dr Paul Bishop for advice about immunofluorescence; Dr. Andrew Herman and Lorena Sueiro Ballesteros for the flow cytometry; and the University of Bristol Genomics Facility for the RNA sequencing work. This work was funded by the Children’s Cancer and Leukaemia Group / Little Princess Trust Project Grant programme (award reference: CCLGA 2017 11), Children with Cancer UK (code: 2012/135), CLIC Sargent UK and the John James Bristol Foundation. Esrp1/2

Publisher Copyright:
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies

Keywords

  • DNA methylation
  • epigenetics
  • ESRP2
  • MET
  • Wilms tumour

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