EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness.
Adenosine
/ analogs & derivatives
Adrenal Cortex Neoplasms
/ genetics
Adrenocortical Carcinoma
/ genetics
Animals
Cell Cycle Proteins
/ genetics
Cell Proliferation
/ drug effects
Chromatin Immunoprecipitation
Computational Biology
E2F1 Transcription Factor
/ genetics
Enhancer of Zeste Homolog 2 Protein
/ antagonists & inhibitors
Gene Expression Regulation, Neoplastic
Humans
Indoles
/ pharmacology
Mice, Knockout
Multivariate Analysis
Proportional Hazards Models
Ribonucleoside Diphosphate Reductase
/ antagonists & inhibitors
Securin
/ genetics
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
07
03
2019
accepted:
11
07
2019
revised:
03
07
2019
pubmed:
1
8
2019
medline:
6
6
2020
entrez:
1
8
2019
Statut:
ppublish
Résumé
EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription. We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis. We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC. Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness.
Sections du résumé
BACKGROUND
EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription.
METHODS
We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis.
RESULTS
We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC.
CONCLUSIONS
Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness.
Identifiants
pubmed: 31363169
doi: 10.1038/s41416-019-0538-y
pii: 10.1038/s41416-019-0538-y
pmc: PMC6738105
doi:
Substances chimiques
Cell Cycle Proteins
0
E2F1 Transcription Factor
0
E2F1 protein, human
0
GW8510
0
Indoles
0
PRC1 protein, human
0
Securin
0
pituitary tumor-transforming protein 1, human
0
3-deazaneplanocin
544SH4020S
ribonucleotide reductase M2
EC 1.17.4.-
Ribonucleoside Diphosphate Reductase
EC 1.17.4.1
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Ezh2 protein, mouse
EC 2.1.1.43
Adenosine
K72T3FS567
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
384-394Références
Cancer Cell. 2016 May 9;29(5):723-736
pubmed: 27165744
Nat Genet. 2014 Jun;46(6):607-12
pubmed: 24747642
Mol Cancer Res. 2014 Oct;12(10):1388-97
pubmed: 24916103
Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12265-E12274
pubmed: 30541888
Am J Cancer Res. 2016 Sep 01;6(9):2041-2053
pubmed: 27725909
Mol Ther Nucleic Acids. 2018 Sep 7;12:805-816
pubmed: 30153565
J Cell Physiol. 2018 Oct;233(10):6759-6767
pubmed: 29667764
Cell Death Differ. 2008 Jan;15(1):202-12
pubmed: 17962814
Science. 2005 Oct 14;310(5746):306-10
pubmed: 16224021
Clin Sci (Lond). 2013 May;124(9):567-78
pubmed: 23113760
Gut. 2016 Sep;65(9):1522-34
pubmed: 26941395
Biochim Biophys Acta. 2010 Apr;1805(2):141-52
pubmed: 20122995
BMC Cancer. 2014 Sep 11;14:664
pubmed: 25213022
Science. 1999 Jul 16;285(5426):418-22
pubmed: 10411507
Mol Biol Cell. 2013 Jun;24(12):1964-73
pubmed: 23615441
Invest New Drugs. 2013 Jun;31(3):685-95
pubmed: 22847785
Front Cell Dev Biol. 2015 Jul 03;3:45
pubmed: 26191527
Surgery. 2013 Dec;154(6):1405-16; discussion 1416
pubmed: 24238056
Mol Cancer Res. 2016 Feb;14(2):163-172
pubmed: 26659825
Neoplasia. 2010 Oct;12(10):807-17
pubmed: 20927319
Cancer Res. 2008 Aug 1;68(15):6292-9
pubmed: 18676853
Nature. 2011 Jan 20;469(7330):343-9
pubmed: 21248841
Hum Mol Genet. 2016 Jul 1;25(13):2789-2800
pubmed: 27149985
Oncogene. 2007 Aug 16;26(38):5596-605
pubmed: 17353909
Mol Endocrinol. 1997 Apr;11(4):433-41
pubmed: 9092795
Cancer Cell. 2013 Jun 10;23(6):839-52
pubmed: 23684459
Mol Clin Oncol. 2015 Mar;3(2):387-391
pubmed: 25798272
Oncol Rep. 2018 Jul;40(1):355-360
pubmed: 29749541
Curr Cancer Drug Targets. 2006 Aug;6(5):409-31
pubmed: 16918309
J Mol Biol. 2017 Jun 30;429(13):1978-1993
pubmed: 27742591
Oncogene. 2017 Aug;36(31):4445-4456
pubmed: 28368424
Trends Cell Biol. 2013 Feb;23(2):54-63
pubmed: 23103209
Science. 2012 Dec 14;338(6113):1465-9
pubmed: 23239736
Nat Commun. 2016 Sep 14;7:12751
pubmed: 27624192
Clin Cancer Res. 2009 Jan 15;15(2):668-76
pubmed: 19147773
Mol Cancer. 2017 Jun 24;16(1):108
pubmed: 28646916
Hum Mol Genet. 2010 Apr 15;19(8):1561-76
pubmed: 20106872
Cell Death Discov. 2016 May 09;2:16027
pubmed: 27551518
PLoS One. 2012;7(8):e44171
pubmed: 22952916
PLoS One. 2012;7(10):e44294
pubmed: 23056178
Annu Rev Biochem. 2006;75:681-706
pubmed: 16756507
J Clin Endocrinol Metab. 2013 Feb;98(2):505-7
pubmed: 23295462
J Clin Oncol. 2009 Mar 1;27(7):1108-15
pubmed: 19139432