UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma.
DNMT1
Epigenetics
Malignant pleural mesothelioma
Prognosis
Therapeutic target
UHRF1
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
09
04
2020
revised:
21
08
2020
accepted:
31
08
2020
pubmed:
15
9
2020
medline:
2
4
2021
entrez:
14
9
2020
Statut:
ppublish
Résumé
Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression. UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM. UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.
Identifiants
pubmed: 32927122
pii: S1556-0864(20)30716-4
doi: 10.1016/j.jtho.2020.08.024
pmc: PMC7775915
mid: NIHMS1636367
pii:
doi:
Substances chimiques
CCAAT-Enhancer-Binding Proteins
0
UHRF1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Uhrf1 protein, mouse
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
89-103Subventions
Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA120528
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011115
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Références
Carcinogenesis. 2019 Jun 10;40(4):529-536
pubmed: 30649229
Biochem Biophys Res Commun. 2017 Aug 26;490(3):707-712
pubmed: 28634077
Cancer Chemother Pharmacol. 2012 Apr;69(4):1079-87
pubmed: 22205202
Cell Discov. 2016 Apr 12;2:16007
pubmed: 27462454
Tumour Biol. 2017 Feb;39(2):1010428317692205
pubmed: 28218043
Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9008-9013
pubmed: 30975761
Br J Cancer. 2010 Jul 13;103(2):217-22
pubmed: 20517312
PLoS Genet. 2017 Oct 4;13(10):e1007042
pubmed: 28976982
J Thorac Oncol. 2018 Nov;13(11):1655-1667
pubmed: 30266660
Oncotarget. 2016 Sep 6;7(36):57821-57831
pubmed: 27507047
Clin Epigenetics. 2019 May 7;11(1):70
pubmed: 31064417
Oncotarget. 2017 Apr 24;8(31):51946-51962
pubmed: 28881702
J Biol Chem. 2017 Mar 3;292(9):3729-3739
pubmed: 28100769
Sci Rep. 2019 Jan 29;9(1):907
pubmed: 30696879
Front Oncol. 2019 Apr 12;9:262
pubmed: 31032225
Genes Chromosomes Cancer. 2018 Nov;57(11):573-583
pubmed: 30338612
Cancer Cell. 2019 Apr 15;35(4):633-648.e7
pubmed: 30956060
Cold Spring Harb Perspect Biol. 2016 Sep 01;8(9):
pubmed: 27194046
Clin Lung Cancer. 2018 Nov;19(6):e901-e912
pubmed: 30224273
Nature. 1998 Sep 3;395(6697):89-93
pubmed: 9738504
Cancer Cell. 2014 Feb 10;25(2):196-209
pubmed: 24486181
J Thorac Oncol. 2018 Nov;13(11):1638-1654
pubmed: 30121394
J Exp Clin Cancer Res. 2016 Nov 14;35(1):174
pubmed: 27839516
Nat Med. 2004 Dec;10(12):1321-8
pubmed: 15558054
Cancer Res. 2010 Jul 15;70(14):5829-39
pubmed: 20587513
J Med Chem. 2013 Jul 25;56(14):5979-83
pubmed: 23808545
Transl Lung Cancer Res. 2017 Jun;6(3):350-365
pubmed: 28713680
Transl Lung Cancer Res. 2018 Oct;7(5):574-583
pubmed: 30450296
Clin Cancer Res. 2016 Mar 1;22(5):1197-210
pubmed: 26459178
Mol Cell. 2016 Jun 16;62(6):848-861
pubmed: 27237052
Int J Radiat Biol. 2011 Mar;87(3):263-73
pubmed: 21067293
Genes (Basel). 2019 Jan 18;10(1):
pubmed: 30669400
Onco Targets Ther. 2019 Jan 11;12:549-559
pubmed: 30666134
J Proteome Res. 2019 Mar 1;18(3):1032-1042
pubmed: 30672294
Nat Commun. 2016 Jan 05;7:10201
pubmed: 26727879
Cell Cycle. 2014;13(4):652-65
pubmed: 24345738
Genome Res. 2017 Apr;27(4):533-544
pubmed: 28232479
Occup Environ Med. 2017 Dec;74(12):851-858
pubmed: 28866609
Cell Commun Signal. 2019 Jul 25;17(1):82
pubmed: 31345225
Br J Cancer. 2003 Jul 7;89(1):120-7
pubmed: 12838312
Epigenetics. 2014 Sep;9(9):1280-9
pubmed: 25147916
High Throughput. 2018 Jul 27;7(3):
pubmed: 30060501
Biochem Pharmacol. 2013 Dec 15;86(12):1643-9
pubmed: 24134914
Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):E142-E151
pubmed: 27956603
J Thorac Oncol. 2016 Oct;11(10):1615-26
pubmed: 27282309
Clin Cancer Res. 2012 Jan 1;18(1):77-90
pubmed: 22028491
Expert Rev Respir Med. 2015 Oct;9(5):633-54
pubmed: 26308799
Dev Biol. 2016 Apr 1;412(1):99-113
pubmed: 26851214
J Clin Oncol. 2018 Oct 1;36(28):2863-2871
pubmed: 30113886