Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumors.
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
04 05 2022
04 05 2022
Historique:
received:
28
07
2021
revised:
20
12
2021
accepted:
10
02
2022
pubmed:
6
3
2022
medline:
6
5
2022
entrez:
5
3
2022
Statut:
ppublish
Résumé
Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. We, therefore, determined whether targeting distinct histone modifier activities was an effective approach for treating AT/RT. The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. Overall, histones H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is, therefore, a potential combination therapy for AT/RT.
Identifiants
pubmed: 35247919
pii: 681957
doi: 10.1158/1535-7163.MCT-21-0646
pmc: PMC9081147
mid: NIHMS1783719
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Histones
0
Nuclear Proteins
0
Transcription Factors
0
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
715-726Subventions
Organisme : NCI NIH HHS
ID : K99 CA234434
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197569
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS093079
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS126513
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA214035
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR075049
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
Références
Nat Med. 2017 Apr;23(4):493-500
pubmed: 28263307
Oncotarget. 2017 Jun 21;8(49):84986-84995
pubmed: 29156698
Clin Cancer Res. 2019 Dec 15;25(24):7331-7339
pubmed: 31471312
PLoS One. 2010 Nov 15;5(11):e13984
pubmed: 21085593
Neuro Oncol. 2013 Feb;15(2):149-60
pubmed: 23190500
Cell Rep. 2019 Nov 19;29(8):2338-2354.e7
pubmed: 31708418
Nature. 1998 Jul 9;394(6689):203-6
pubmed: 9671307
Pediatr Blood Cancer. 2017 Mar;64(3):
pubmed: 27555605
Mol Cell Biol. 2008 May;28(10):3457-64
pubmed: 18332116
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Trends Immunol. 2020 Oct;41(10):948-963
pubmed: 32976740
Nat Commun. 2019 Apr 3;10(1):1523
pubmed: 30944313
Bioinformatics. 2016 Sep 15;32(18):2866-8
pubmed: 27153664
Neuro Oncol. 2020 Jul 7;22(7):944-954
pubmed: 32129445
Cancer Cell. 2016 Dec 12;30(6):891-908
pubmed: 27960086
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Cancer Res. 1999 Jan 1;59(1):74-9
pubmed: 9892189
Oncogene. 2015 Jan 2;34(1):119-28
pubmed: 24276244
Neuro Oncol. 2020 May 15;22(5):613-624
pubmed: 31889194
Transl Oncol. 2020 Jun;13(6):100773
pubmed: 32334405
Cell. 2011 Sep 16;146(6):904-17
pubmed: 21889194
Trends Biochem Sci. 2004 Aug;29(8):409-17
pubmed: 15362224
Int J Cancer. 2019 Apr 15;144(8):1983-1995
pubmed: 30230537
Bioinformatics. 2009 Apr 15;25(8):1091-3
pubmed: 19237447
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Nat Med. 2014 Jul;20(7):732-40
pubmed: 24973920
Nat Med. 2010 Dec;16(12):1429-33
pubmed: 21076395
Nature. 2012 Dec 6;492(7427):108-12
pubmed: 23051747
Curr Oncol Rep. 2004 Nov;6(6):445-52
pubmed: 15485613
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nat Med. 2018 Jul;24(7):1047-1057
pubmed: 29892061
Acta Neuropathol. 2017 Nov;134(5):817-818
pubmed: 28815304
Nat Chem Biol. 2012 Nov;8(11):890-6
pubmed: 23023262
J Interferon Cytokine Res. 2015 Dec;35(12):963-8
pubmed: 26308599
Expert Opin Ther Targets. 2018 Apr;22(4):365-379
pubmed: 29528755
Neuro Oncol. 2010 Apr;12(4):366-76
pubmed: 20308314
Lancet Oncol. 2018 May;19(5):649-659
pubmed: 29650362
Nature. 2018 Mar 22;555(7697):469-474
pubmed: 29539639
Mol Cancer Ther. 2014 Apr;13(4):842-54
pubmed: 24563539
Neurosurgery. 2020 Nov 16;87(6):E680-E688
pubmed: 32674144
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7
pubmed: 23620515
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nature. 2010 Dec 23;468(7327):1067-73
pubmed: 20871596
Neuro Oncol. 2016 Nov;18(11):1519-1528
pubmed: 27370397
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Cancer Cell. 2019 Jan 14;35(1):95-110.e8
pubmed: 30595504
Cancer Cell. 2010 Oct 19;18(4):316-28
pubmed: 20951942
Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360-5
pubmed: 23236167
Cell. 2018 Sep 20;175(1):186-199.e19
pubmed: 30220457
Cancer Res Treat. 2021 Apr;53(2):378-388
pubmed: 33138347
Clin Cancer Res. 2002 Nov;8(11):3461-7
pubmed: 12429635
Cancer Discov. 2012 May;2(5):405-13
pubmed: 22588878
EMBO Rep. 2000 Dec;1(6):500-6
pubmed: 11263494
Nat Med. 2016 Feb;22(2):128-34
pubmed: 26845405
Nat Genet. 2017 Feb;49(2):289-295
pubmed: 27941797
Cancer Cell. 2016 Mar 14;29(3):379-393
pubmed: 26923874