MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency

Russell Moser, Masafumi Toyoshima, Kristin Robinson, Kay E. Gurley, Heather L. Howie, Jerry Davison, Martin Morgan, Christopher J. Kemp, Carla Grandori

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

MYC-induced DNA damage is exacerbated in WRN-deficient cells, leading to replication stress and accelerated cellular senescence. To determine whether WRN deficiency impairs MYC-driven tumor development, we used both xenograft and autochthonous tumor models. Conditional silencing of WRN expression in c-MYC overexpressing non-small cell lung cancer xenografts impaired both tumor establishment and tumor growth. This inhibitory effect of WRN knockdown was accompanied by increased DNA damage, decreased proliferation, and tumor necrosis. In the Eμ-Myc mouse model of B-cell lymphoma, a germline mutation in the helicase domain of Wrn (Wrn δhel/δhel) resulted in a significant delay in emergence of lethal lymphomas, extending tumor-free survival by more than 30%. Analysis of preneoplastic B cells from Eμ-Myc Wrn mutant mice revealed increased DNA damage, elevation of senescence markers, and decreased proliferation in comparison with cells from age-matched Em-Myc mice. Immunohistochemical and global gene expression analysis of overt Eμ-Myc Wrnδhel/δhel lymphomas showed a marked increase in expression of the CDK inhibitor, p16 Ink4a, as well as elevation of TAp63, a known mediator of senescence. Collectively, these studies show that in the context of Myc-associated tumorigenesis, loss of Wrn amplifies the DNA damage response, both in preneoplastic and neoplastic tissue, engaging activation of tumor suppressor pathways. This leads to inhibition of tumor growth and prolonged tumor-free survival. Targeting WRN or its enzymatic function could prove to be an effective strategy in the treatment of MYC-associated cancers.

Original languageEnglish
Pages (from-to)535-545
Number of pages11
JournalMolecular Cancer Research
Volume10
Issue number4
DOIs
Publication statusPublished - 2012 Apr

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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