Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing.
The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery-an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Str, Athens GR-11527, Greece.
Panagiotis
P
Galanos
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou St., Athens GR-11527, Greece.
Konstantinos
K
Vougas
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark.
David
0000-0003-4363-0339
D
Walter
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou St., Athens GR-11527, Greece.
Alexander
A
Polyzos
Genome Integrity Unit, Danish Cancer Society Research Centre, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
Apolinar
A
Maya-Mendoza
Centre for Gene Regulation &Expression, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Emma J
EJ
Haagensen
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou St., Athens GR-11527, Greece.
Antonis
A
Kokkalis
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou St., Athens GR-11527, Greece.
Fani-Marlen
FM
Roumelioti
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou St., Athens GR-11527, Greece.
Sarantis
S
Gagos
Department of Medical Genetics, Medical School, University of Athens, Thivon &Levadias Str., Athens GR-11527, Greece.
Maria
M
Tzetis
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
Begoña
B
Canovas
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
Ana
A
Igea
Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland.
Akshay K
AK
Ahuja
Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland.
Ralph
R
Zellweger
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Str, Athens GR-11527, Greece.
Sofia
S
Havaki
Department of Medical Genetics, Medical School, University of Athens, Thivon &Levadias Str., Athens GR-11527, Greece.|Research Institute for the Study of Genetic and Malignant Disorders in Childhood, Aghia Sophia Children's Hospital, Thivon Str., Athens GR-11527, Greece.
Emanuel
E
Kanavakis
Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research 'Demokritos', Agia Paraskevi Attikis, PO Box 60228, Athens GR-153 10, Greece.
Dimitris
D
Kletsas
Center for Targeted Therapeutics, Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Coker Life Science Building, 715 Sumter Street, Columbia, South Carolina 29208, USA.
Igor B
IB
Roninson
Cancer and Clinical Experimental Science Units, Faculty of Medicine, Institute for Life Sciences, Center for Proteome Research, University of Southampton, University Road Southampton, Southampton SO17 1BJ, UK.
Spiros D
SD
Garbis
Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland.
Massimo
M
Lopes
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
Angel
A
Nebreda
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou St., Athens GR-11527, Greece.
Dimitris
D
Thanos
Centre for Gene Regulation &Expression, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
J Julian
0000-0002-9524-5849
JJ
Blow
Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester M20 4QL, UK.
Paul
P
Townsend
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaloes Vej 5, Copenhagen DK-2200, Denmark.
Claus Storgaard
CS
Sørensen
Genome Integrity Unit, Danish Cancer Society Research Centre, Strandboulevarden 49, Copenhagen DK-2100, Denmark.|Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hněvotínská, Olomouc 1333/5 779 00, Czech Republic.|Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm SE-171 77, Sweden.
Jiri
J
Bartek
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, 75 Mikras Asias Str, Athens GR-11527, Greece.|Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou St., Athens GR-11527, Greece.|Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Wilmslow Road, Manchester M20 4QL, UK.
Vassilis G
VG
Gorgoulis
D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53