SUV39H1 Represses the Expression of Cytotoxic T-Lymphocyte Effector Genes to Promote Colon Tumor Immune Evasion.
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Colonic Neoplasms
/ drug therapy
Disease Models, Animal
Enzyme Inhibitors
/ pharmacology
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Histones
/ metabolism
Humans
Lymphocytes, Tumor-Infiltrating
/ drug effects
Methyltransferases
/ antagonists & inhibitors
Mice
Repressor Proteins
/ antagonists & inhibitors
T-Lymphocytes, Cytotoxic
/ drug effects
Tumor Escape
Tumor Microenvironment
/ drug effects
Journal
Cancer immunology research
ISSN: 2326-6074
Titre abrégé: Cancer Immunol Res
Pays: United States
ID NLM: 101614637
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
28
02
2018
revised:
07
08
2018
accepted:
18
12
2018
pubmed:
6
1
2019
medline:
21
5
2020
entrez:
6
1
2019
Statut:
ppublish
Résumé
Despite the presence of CTLs in the tumor microenvironment, the majority of immunogenic human colon cancer does not respond to immune checkpoint inhibitor immunotherapy, and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unknown. We report here that CTLs were present in both MSI and microsatellite stable colon tumors. The expression of the H3K9me3-specific histone methyltransferase SUV39H1 was significantly elevated in human colon carcinoma compared with normal colon tissues. Using a mouse colon carcinoma model, we further determined that tumor-infiltrating CTLs in the colon tumor microenvironment have high expression of SUV39H1. To target SUV39H1 in the tumor microenvironment, a virtual chemical library was screened on the basis of the SET (suppressor of variegation 3-9, enhancer of zeste and trithorax) domain structure of the human SUV39H1 protein. Functional enzymatic activity assays identified a small molecule that inhibits SUV39H1 enzymatic activity. On the basis of the structure of this small molecule, we modified it and chemically synthesized a small molecule, termed F5446, which has an EC
Identifiants
pubmed: 30610059
pii: 2326-6066.CIR-18-0126
doi: 10.1158/2326-6066.CIR-18-0126
pmc: PMC6397681
mid: NIHMS1517449
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Histones
0
Repressor Proteins
0
SUV39H1 protein, human
EC 2.1.1.
Methyltransferases
EC 2.1.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
414-427Subventions
Organisme : NCI NIH HHS
ID : R01 CA182518
Pays : United States
Organisme : CSRD VA
ID : I01 CX001364
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA236436
Pays : United States
Organisme : NCI NIH HHS
ID : K12 CA133250
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
Organisme : NCI NIH HHS
ID : R43 CA221414
Pays : United States
Organisme : BLRD VA
ID : IS1 BX004009
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227433
Pays : United States
Organisme : BLRD VA
ID : I01 BX001962
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA133085
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
Références
Science. 1994 Jul 22;265(5171):528-30
pubmed: 7518614
Oncogene. 2016 Feb 11;35(6):793-9
pubmed: 25961932
Nat Immunol. 2012 Jul 01;13(8):770-7
pubmed: 22751139
Oncoimmunology. 2016 Apr 25;5(7):e1151595
pubmed: 27622016
Nature. 2001 Apr 26;410(6832):1107-11
pubmed: 11323675
N Engl J Med. 2015 Jun 25;372(26):2509-20
pubmed: 26028255
BMC Cancer. 2018 Feb 6;18(1):149
pubmed: 29409480
Cancer Res. 1998 Feb 1;58(3):526-34
pubmed: 9458101
Cancer Res. 2009 Mar 15;69(6):2685-93
pubmed: 19258510
Mol Cell. 2003 Dec;12(6):1591-8
pubmed: 14690610
Annu Rev Immunol. 2002;20:323-70
pubmed: 11861606
J Comput Chem. 2010 Jan 30;31(2):455-61
pubmed: 19499576
N Engl J Med. 2005 Dec 22;353(25):2654-66
pubmed: 16371631
J Cheminform. 2011 Oct 07;3:33
pubmed: 21982300
Science. 2018 Jan 12;359(6372):177-186
pubmed: 29326266
Cancer Res. 2017 Jan 15;77(2):401-411
pubmed: 27872097
Nucleic Acids Res. 2016 May 5;44(8):3586-94
pubmed: 26673699
Nat Med. 2014 Mar;20(3):283-90
pubmed: 24487434
Oncoimmunology. 2015 Jun 5;4(7):e1058597
pubmed: 26140250
Immunity. 2000 Aug;13(2):265-76
pubmed: 10981969
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
J Natl Cancer Inst. 2018 Jan 1;110(1):
pubmed: 28922790
Nature. 2009 Oct 1;461(7264):659-63
pubmed: 19794494
Science. 2006 Sep 29;313(5795):1960-4
pubmed: 17008531
Gut. 1995 Dec;37(6):819-25
pubmed: 8537054
Gut. 2017 Aug;66(8):1463-1473
pubmed: 27196573
Nature. 2012 Jul 12;487(7406):249-53
pubmed: 22763435
Immunity. 2014 Nov 20;41(5):853-65
pubmed: 25517617
Cancer Discov. 2015 Jan;5(1):43-51
pubmed: 25358689
Cancer Res. 2007 Mar 1;67(5):1883-6
pubmed: 17332313
Nature. 2000 Aug 10;406(6796):593-9
pubmed: 10949293
J Immunol. 2015 Aug 15;195(4):1868-82
pubmed: 26136424
Nat Chem Biol. 2005 Aug;1(3):143-5
pubmed: 16408017
Cancer Res. 2011 Feb 15;71(4):1263-71
pubmed: 21303976
Annu Rev Cell Dev Biol. 2010;26:471-501
pubmed: 19575672
Gut. 2005 May;54(5):661-5
pubmed: 15831912
J Biol Chem. 2016 Apr 29;291(18):9690-9
pubmed: 26953344
Gastroenterology. 1997 Jul;113(1):160-7
pubmed: 9207274
Cancer Res. 1999 Oct 15;59(20):5106-11
pubmed: 10537283
Cancer Res. 2011 Sep 1;71(17):5601-5
pubmed: 21846822
Cancer Immunol Res. 2017 Nov;5(11):942-949
pubmed: 29038296
PLoS One. 2012;7(12):e52977
pubmed: 23285239
J Natl Cancer Inst. 2018 Jan 1;110(1):
pubmed: 28922789
Int J Cancer. 1994 May 1;57(3):371-7
pubmed: 8168998
Cancer Cell. 2014 Jun 16;25(6):846-59
pubmed: 24898549
Nat Chem Biol. 2016 Mar;12(3):188-93
pubmed: 26807716
J Exp Med. 2017 Apr 3;214(4):895-904
pubmed: 28302645
Nat Rev Immunol. 2012 Mar 22;12(4):253-68
pubmed: 22437938