The EZH2 inhibitor tazemetostat upregulates the expression of CCL17/TARC in B-cell lymphoma and enhances T-cell recruitment.
Benzamides
/ pharmacology
Biphenyl Compounds
/ pharmacology
Cell Line, Tumor
Cell Movement
Chemokine CCL17
/ genetics
Databases, Factual
Enhancer of Zeste Homolog 2 Protein
/ antagonists & inhibitors
Humans
Jumonji Domain-Containing Histone Demethylases
/ genetics
Lymphocytes, Tumor-Infiltrating
Lymphoma, Large B-Cell, Diffuse
/ drug therapy
Morpholines
/ pharmacology
Promoter Regions, Genetic
Pyridones
/ pharmacology
Reed-Sternberg Cells
Tumor Microenvironment
/ drug effects
Up-Regulation
B-cell lymphoma
CCL17
EZH2 inhibitor
Hodgkin lymphoma
tumor microenvironment
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
revised:
25
08
2021
received:
21
05
2021
accepted:
26
08
2021
pubmed:
28
8
2021
medline:
24
11
2021
entrez:
27
8
2021
Statut:
ppublish
Résumé
An inhibitor of the histone methyltransferase enhancer of zeste homologue 2 (EZH2), tazemetostat, has been developed for the treatment of B-cell lymphoma, but its mechanisms of action are not fully elucidated. We screened for genes targeted by tazemetostat in eleven B-cell lymphoma cell lines and found that tazemetostat significantly increased the expression of chemokine (C-C motif) ligand 17 (CCL17)/thymus- and activation-regulated chemokine (TARC) in all, which codes for a chemokine that is a hallmark of Hodgkin/Reed-Sternberg (H/RS) cells in Hodgkin lymphoma. Notably, gene set enrichment analysis demonstrated a positive correlation between the genes upregulated by tazemetostat in five follicular lymphoma (FL) cell lines and those reported to be overexpressed in H/RS cells. The CCL17 promoter region was enriched in repressive histone modification H3K27me3, and tazemetostat induced H3K27 demethylation and activated gene transcription. CCL17 protein secretion was also induced by EZH2 inhibition, which was further enhanced by concurrent CpG stimulation. In vitro transwell migration assay demonstrated that CCL17 produced by tazemetostat-treated B cells enhanced the recruitment of T cells, which had the potential to exert antilymphoma response. Analysis of publicly available human lymphoma databases showed that CCL17 gene expression was inversely correlated with the EZH2 activation signature and significantly paralleled the CD4
Identifiants
pubmed: 34449935
doi: 10.1111/cas.15122
pmc: PMC8586691
doi:
Substances chimiques
Benzamides
0
Biphenyl Compounds
0
CCL17 protein, human
0
Chemokine CCL17
0
KDM4C protein, human
0
Morpholines
0
Pyridones
0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
tazemetostat
Q40W93WPE1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4604-4616Subventions
Organisme : Japan Society for the Promotion of Science
ID : 15K09474
Organisme : Japan Society for the Promotion of Science
ID : 18K08324
Informations de copyright
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Références
J Clin Oncol. 2018 May 10;36(14):1428-1439
pubmed: 29584546
Blood. 2003 Apr 1;101(7):2789-96
pubmed: 12456498
Pathol Int. 2012 Aug;62(8):518-24
pubmed: 22827759
J Exp Med. 2001 Sep 17;194(6):863-9
pubmed: 11561001
Leukemia. 2011 Apr;25(4):726-9
pubmed: 21233829
Lancet Oncol. 2014 Sep;15(10):e435-46
pubmed: 25186047
Nat Protoc. 2006;1(2):729-48
pubmed: 17406303
J Exp Med. 1996 Oct 1;184(4):1495-505
pubmed: 8879220
Nat Genet. 2010 Feb;42(2):181-5
pubmed: 20081860
Nat Rev Cancer. 2009 Jan;9(1):15-27
pubmed: 19078975
N Engl J Med. 1999 Apr 22;340(16):1239-47
pubmed: 10210707
Cancer Cell. 2013 May 13;23(5):677-92
pubmed: 23680150
Cancer Sci. 2003 Sep;94(9):774-81
pubmed: 12967475
PLoS One. 2011;6(12):e28585
pubmed: 22194861
Lancet Oncol. 2015 Sep;16(9):1111-1122
pubmed: 26256760
Blood. 2002 Aug 15;100(4):1425-9
pubmed: 12149227
Nat Genet. 2012 Dec;44(12):1316-20
pubmed: 23143595
Mol Immunol. 2020 Mar;119:35-45
pubmed: 31962268
Lancet. 1964 Feb 1;1(7327):238-40
pubmed: 14086209
Cancer Cell. 2012 Oct 16;22(4):506-523
pubmed: 23079660
Mol Med. 2001 May;7(5):285-92
pubmed: 11474574
J Clin Oncol. 2016 Aug 10;34(23):2698-704
pubmed: 27269947
Nature. 2012 Dec 6;492(7427):108-12
pubmed: 23051747
J Clin Oncol. 1999 Dec;17(12):3804-9
pubmed: 10577852
Leukemia. 1997 Jan;11(1):64-72
pubmed: 9001420
Tohoku J Exp Med. 1988 Dec;156(4):319-30
pubmed: 2854303
Nat Rev Cancer. 2019 Apr;19(4):215-227
pubmed: 30867580
Cancer Discov. 2016 Aug;6(8):827-37
pubmed: 27301722
Nat Chem Biol. 2012 Nov;8(11):890-6
pubmed: 23023262
Mol Cancer Ther. 2014 Dec;13(12):3062-73
pubmed: 25253781
Nature. 2014 Nov 27;515(7528):568-71
pubmed: 25428505
Cancer Res. 1968 Jul;28(7):1300-10
pubmed: 4174339
Br J Haematol. 2001 Mar;112(4):950-8
pubmed: 11298590
Eur J Haematol. 2004 Sep;73(3):210-4
pubmed: 15287919
Blood. 2000 Feb 15;95(4):1443-50
pubmed: 10666223
Lancet Oncol. 2018 May;19(5):649-659
pubmed: 29650362
Nat Rev Cancer. 2009 Nov;9(11):773-84
pubmed: 19851313
J Clin Exp Hematop. 2007 Apr;47(1):9-13
pubmed: 17510532
J Clin Oncol. 2017 Jul 1;35(19):2125-2132
pubmed: 28441111
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Cancer Cell. 2010 Dec 14;18(6):590-605
pubmed: 21156283
Cell. 2017 Oct 5;171(2):481-494.e15
pubmed: 28985567
J Allergy Clin Immunol. 2003 Jun;111(6):1185-99; quiz 1200
pubmed: 12789214
J Clin Oncol. 2019 Feb 20;37(6):481-489
pubmed: 30620669
Am J Clin Pathol. 2006 Aug;126(2):222-9
pubmed: 16891197
Cancer. 1978 Nov;42(5):2379-91
pubmed: 214220
Immunol Rev. 2006 Apr;210:67-85
pubmed: 16623765
Blood. 2012 Oct 25;120(17):3530-40
pubmed: 22955918
Cancer Sci. 2021 Nov;112(11):4604-4616
pubmed: 34449935
Cancer Sci. 2021 Mar;112(3):1123-1131
pubmed: 33492746
Lancet Oncol. 2020 Nov;21(11):1433-1442
pubmed: 33035457
N Engl J Med. 2015 Jan 22;372(4):311-9
pubmed: 25482239
J Clin Oncol. 2011 May 10;29(14):1812-26
pubmed: 21483001
Nat Rev Immunol. 2004 Mar;4(3):211-22
pubmed: 15039758
Immunity. 2009 Jun 19;30(6):899-911
pubmed: 19464196