The MDM2 inducible promoter folds into four-tetrad antiparallel G-quadruplexes targetable to fight malignant liposarcoma.
Apoptosis
Cell Cycle
Cell Line, Tumor
Computer Simulation
G-Quadruplexes
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Ligands
Liposarcoma
/ therapy
Models, Genetic
Molecular Targeted Therapy
Neoplasm Proteins
/ metabolism
Nuclear Proteins
/ metabolism
Promoter Regions, Genetic
/ genetics
Protein Interaction Mapping
Proteolysis
Proto-Oncogene Proteins c-mdm2
/ biosynthesis
Soft Tissue Neoplasms
/ therapy
Tumor Suppressor Protein p53
/ metabolism
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
25 01 2021
25 01 2021
Historique:
accepted:
21
12
2020
revised:
18
12
2020
received:
29
02
2020
pubmed:
8
1
2021
medline:
4
2
2021
entrez:
7
1
2021
Statut:
ppublish
Résumé
Well-differentiated liposarcoma (WDLPS) is a malignant neoplasia hard to diagnose and treat. Its main molecular signature is amplification of the MDM2-containing genomic region. The MDM2 oncogene is the master regulator of p53: its overexpression enhances p53 degradation and inhibits apoptosis, leading to the tumoral phenotype. Here, we show that the MDM2 inducible promoter G-rich region folds into stable G-quadruplexes both in vitro and in vivo and it is specifically recognized by cellular helicases. Cell treatment with G-quadruplex-ligands reduces MDM2 expression and p53 degradation, thus stimulating cancer cell cycle arrest and apoptosis. Structural characterization of the MDM2 G-quadruplex revealed an extraordinarily stable, unique four-tetrad antiparallel dynamic conformation, amenable to selective targeting. These data indicate the feasibility of an out-of-the-box G-quadruplex-targeting approach to defeat WDLPS and all tumours where restoration of wild-type p53 is sought. They also point to G-quadruplex-dependent genomic instability as possible cause of MDM2 expansion and WDLPS tumorigenesis.
Identifiants
pubmed: 33410915
pii: 6067396
doi: 10.1093/nar/gkaa1273
pmc: PMC7826256
doi:
Substances chimiques
Ligands
0
Neoplasm Proteins
0
Nuclear Proteins
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
847-863Subventions
Organisme : European Research Council
ID : 615879
Pays : International
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
ACS Cent Sci. 2015 Aug 26;1(5):226-233
pubmed: 26405692
PLoS One. 2014 Aug 01;9(8):e103876
pubmed: 25084283
J Am Chem Soc. 2009 Apr 1;131(12):4301-9
pubmed: 19271707
J Biol Chem. 2003 Jul 11;278(28):25716-21
pubmed: 12730202
Elife. 2016 Sep 13;5:
pubmed: 27623008
Sarcoma. 2011;2011:483154
pubmed: 21253554
Genetics. 2018 Mar;208(3):951-961
pubmed: 29279323
Sci Rep. 2015 Nov 13;5:16673
pubmed: 26564809
Cancer Invest. 2015;33(9):440-50
pubmed: 26288114
FEBS J. 2011 Apr;278(6):988-98
pubmed: 21244633
Clin Cancer Res. 2013 Jan 1;19(1):34-41
pubmed: 23262034
FEBS Lett. 2019 Aug;593(16):2083-2102
pubmed: 31325371
Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11250-5
pubmed: 11016968
Histopathology. 2014 Jan;64(1):2-11
pubmed: 24164390
Stem Cell Investig. 2017 Mar 15;4:21
pubmed: 28447036
Lancet Oncol. 2012 Nov;13(11):1133-40
pubmed: 23084521
Ann Oncol. 2012 Jun;23(6):1601-7
pubmed: 22039081
Nature. 2010 Apr 22;464(7292):1214-7
pubmed: 20383123
Nat Genet. 2017 Mar;49(3):367-376
pubmed: 28092686
Acta Biochim Biophys Sin (Shanghai). 2014 Mar;46(3):180-9
pubmed: 24389645
Cancer Res. 2009 Oct 1;69(19):7653-61
pubmed: 19738048
Cell. 2004 Nov 24;119(5):591-602
pubmed: 15550242
Nat Chem Biol. 2017 Jan;13(1):18-20
pubmed: 27820800
J Med Chem. 2018 Oct 11;61(19):8625-8638
pubmed: 30188709
Nat Rev Mol Cell Biol. 2010 Mar;11(3):165-70
pubmed: 20177394
Structure. 1995 Oct 15;3(10):997-1008
pubmed: 8590010
FEBS Lett. 2015 Jun 22;589(14):1653-68
pubmed: 25979174
Nucleic Acids Res. 2015 Oct 15;43(18):8884-97
pubmed: 26354862
Science. 2004 Feb 6;303(5659):844-8
pubmed: 14704432
Cells. 2019 Oct 18;8(10):
pubmed: 31635389
Mol Cell Biol. 2000 Jan;20(2):429-40
pubmed: 10611221
Mol Cell. 2017 Sep 21;67(6):1013-1025.e9
pubmed: 28867293
EMBO Rep. 2016 Sep;17(9):1314-25
pubmed: 27461252
Nat Commun. 2019 Feb 26;10(1):943
pubmed: 30808951
Sci Rep. 2017 Mar 24;7:45244
pubmed: 28338097
Oncogene. 2008 Feb 7;27(7):997-1003
pubmed: 17700533
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11593-8
pubmed: 12195017
Mol Cancer Res. 2003 Dec;1(14):1001-8
pubmed: 14707283
Anal Chem. 2017 Sep 5;89(17):8632-8637
pubmed: 28787153
Nucleic Acids Res. 1995 Jul 25;23(14):2584-92
pubmed: 7651818
J Hematol Oncol. 2017 Jul 3;10(1):133
pubmed: 28673313
Nat Biotechnol. 2015 Aug;33(8):877-81
pubmed: 26192317
Nat Genet. 2016 Oct;48(10):1267-72
pubmed: 27618450
Nucleic Acids Res. 2015 Sep 30;43(17):8590-600
pubmed: 26253741
Cell. 2017 Sep 7;170(6):1062-1078
pubmed: 28886379
Genes Cancer. 2012 Mar;3(3-4):226-39
pubmed: 23150756
Genes Cancer. 2010 Jun;1(6):641-649
pubmed: 21113409
BMC Genomics. 2015 Nov 14;16:929
pubmed: 26573619
J Biol Chem. 2005 Jun 17;280(24):22641-50
pubmed: 15837790
Eur J Cancer. 2005 Dec;41(18):2853-60
pubmed: 16289617
EMBO J. 1994 Oct 17;13(20):4991-5001
pubmed: 7957065
Int J Cancer. 2007 Jul 1;121(1):199-205
pubmed: 17354236
Nucleic Acids Res. 2018 Apr 20;46(7):3270-3283
pubmed: 29554280
Nucleic Acids Res. 2005 May 24;33(9):2908-16
pubmed: 15914667
J Am Chem Soc. 2014 Feb 5;136(5):1750-3
pubmed: 24450880
Mol Cancer Ther. 2011 Jan;10(1):69-79
pubmed: 21075910
Nucleic Acids Res. 2016 May 5;44(8):3481-94
pubmed: 27060139
Nature. 2014 Sep 4;513(7516):65-70
pubmed: 25079319
Biochem Res Int. 2012;2012:808934
pubmed: 22830025
Nat Protoc. 2018 Mar;13(3):551-564
pubmed: 29470465
Mol Cell Biol. 1994 Mar;14(3):1786-95
pubmed: 8114711
J Med Chem. 2015 Dec 24;58(24):9639-52
pubmed: 26599611
FEBS J. 2010 Sep;277(17):3459-69
pubmed: 20670278
Genes Dev. 1994 Aug 1;8(15):1739-49
pubmed: 7958853
Nucleic Acids Res. 2009 Jan;37(1):38-46
pubmed: 19010961
Cancer Res. 2003 May 15;63(10):2616-23
pubmed: 12750288
Nucleic Acids Res. 2018 Nov 30;46(21):11605-11617
pubmed: 30277522
Nature. 2000 Nov 16;408(6810):307-10
pubmed: 11099028
RNA. 2009 Jan;15(1):104-15
pubmed: 19029303
Cancer Cell. 2009 Mar 3;15(3):171-83
pubmed: 19249676
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Cancers (Basel). 2018 Oct 24;10(11):
pubmed: 30352966
Nucleic Acids Res. 2019 May 7;47(8):3862-3874
pubmed: 30892612
Anticancer Res. 2013 Jun;33(6):2597-604
pubmed: 23749914