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MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency.

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 E?-Myc mouse model of B-cell lymphoma, a germline mutation in the helicase domain of Wrn (Wrn(?hel/?hel)) resulted in a significant delay in emergence of lethal lymphomas, extending tumor-free survival by more than 30%. Analysis of preneoplastic B cells from E?-Myc Wrn mutant mice revealed increased DNA damage, elevation of senescence markers, and decreased proliferation in comparison with cells from age-matched E?-Myc mice. Immunohistochemical and global gene expression analysis of overt E?-Myc Wrn(?hel/?hel) 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.

SUBMITTER: Moser R

PROVIDER: S-EPMC3707802 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency.

Moser Russell R Toyoshima Masafumi M Robinson Kristin K Gurley Kay E KE Howie Heather L HL Davison Jerry J Morgan Martin M Kemp Christopher J CJ Grandori Carla C

Molecular cancer research : MCR 20120201 4

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, decreas ...[more]

PMID: 22301954

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Project description:Werner syndrome (WS) is a rare autosomal recessive progeria disease with genetic instability/cancer predisposition, thus a good model in understanding aging related carcinogenesis. Telomere dysfunction induced cellular senescence is essential in the manifestation of the WS phenotype. Our previous data has shown that p21 (encoded by Cdkn1a gene) could induce cellular senescence and suppress cellular growth of ALT (alternative lengthening of telomere) tumors derived from WS, suggested that p21 might play a key role in maintaining senescence of WS cells. To confirm the role of p21 in suppressing telomere dysfunction induced tumorigenesis, we overexpressed dominant negative protein TRF2?B?M in p21-/- mouse embryonic fibroblasts (MEFs). To further stress the cell, we crossed Wrn-/- mice with p21-/- mice to obtained p21-/-Wrn-/- MEFs, and overexpressed TRF2?B?M in these MEFs to induce telomere dysfunction similar to that in WS cells. Our data showed that, in the context of p21-/- TRF2?B?M, loss of p21 function rescued cellular senescence, and induced p53 mutation, but did not induce tumorigenesis. However, in the set of p21-/-Wrn-/- TRF2?B?M, loss of p21 function induced p53 mutation and tumorigenesis. To further verify the role of p21 in suppressing telomere dysfunction related tumorigenesis, we knocked down p21 in non-tumorigenic immortalized cells derived from WS MEFs (mTerc -/-Wrn-/- ), and found that loss of p21 could induce ALT tumorigenesis, which displayed typical smear pattern of telomere length and arc-shaped telomeric DNA. In another hand, recovering telomerase activity in these MEFs could also induce tumorigenesis without affecting p21 expression level. Together our data suggested that p21 controlled cell cycle regulation played an essential role in suppressing telomere dysfunction-related tumorigenesis. These data also suggested that the genetic context is essential in determining the role of p21 in cancer prevention. Therefore, targeting p21 in the treatment of human degenerative diseases would require a personalized genetic background screen.

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MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency.

Publications

MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency.

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