MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency.
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 Eμ-Myc mice. Immunohistochemical and global gene expression analysis of overt Eμ-Myc Wrn(Δhel/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.
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Russell
R
Moser
Masafumi
M
Toyoshima
Kristin
K
Robinson
Kay E
KE
Gurley
Heather L
HL
Howie
Jerry
J
Davison
Martin
M
Morgan
Christopher J
CJ
Kemp
Carla
C
Grandori
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D005838:Genotype; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D053484:RecQ Helicases / Q000172:deficiency / Q000235:genetics*; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase