Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer.
Antineoplastic Agents
/ metabolism
Cancer-Associated Fibroblasts
/ metabolism
Cell Cycle Proteins
/ antagonists & inhibitors
Chromatin
/ metabolism
Chromatin Assembly and Disassembly
Colorectal Neoplasms
/ metabolism
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Interleukin-6
/ metabolism
Interleukin-8
/ metabolism
Janus Kinase 2
/ metabolism
Phosphorylation
Protein Domains
STAT3 Transcription Factor
/ metabolism
Signal Transduction
Transcription Factors
/ antagonists & inhibitors
Tumor Microenvironment
Ubiquitin Thiolesterase
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 07 2021
21 07 2021
Historique:
received:
12
01
2021
accepted:
01
07
2021
entrez:
22
7
2021
pubmed:
23
7
2021
medline:
3
8
2021
Statut:
epublish
Résumé
BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively.
Identifiants
pubmed: 34290255
doi: 10.1038/s41467-021-24687-4
pii: 10.1038/s41467-021-24687-4
pmc: PMC8295257
doi:
Substances chimiques
Antineoplastic Agents
0
BRD4 protein, human
0
CXCL8 protein, human
0
Cell Cycle Proteins
0
Chromatin
0
IL6 protein, human
0
Interleukin-6
0
Interleukin-8
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Transcription Factors
0
JAK2 protein, human
EC 2.7.10.2
Janus Kinase 2
EC 2.7.10.2
UCHL3 protein, human
EC 3.4.19.12
Ubiquitin Thiolesterase
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4441Informations de copyright
© 2021. The Author(s).
Références
Cell Res. 2014 Jul;24(7):809-19
pubmed: 24874954
Cell. 2013 Apr 11;153(2):320-34
pubmed: 23582323
Cell Rep. 2016 Aug 2;16(5):1273-1286
pubmed: 27452461
Cell. 2013 Apr 11;153(2):307-19
pubmed: 23582322
Nat Rev Cancer. 2016 Aug 23;16(9):582-98
pubmed: 27550820
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
J Exp Med. 2018 Nov 5;215(11):2833-2849
pubmed: 30266800
Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):E5352-E5361
pubmed: 28630312
Nat Commun. 2015 Dec 03;6:10091
pubmed: 26631872
Cell. 2010 Mar 19;140(6):883-99
pubmed: 20303878
Nat Med. 2017 Sep;23(9):1055-1062
pubmed: 28805822
Clin Cancer Res. 2011 Mar 15;17(6):1452-62
pubmed: 21310826
Nature. 2015 Sep 24;525(7570):543-547
pubmed: 26367798
Nature. 2011 Jun 15;474(7351):318-26
pubmed: 21677748
Nat Med. 2015 Nov;21(11):1350-6
pubmed: 26457759
Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E5990-E5999
pubmed: 29891662
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Nature. 2016 Jan 21;529(7586):413-417
pubmed: 26735014
Cell Rep. 2018 Feb 27;22(9):2236-2245
pubmed: 29490263
Oncogene. 2017 Aug 31;36(35):4975-4986
pubmed: 28459468
J Biol Chem. 2014 Mar 28;289(13):9304-19
pubmed: 24497639
Cancer Discov. 2018 Jan;8(1):24-36
pubmed: 29263030
Nat Med. 2017 Sep;23(9):1063-1071
pubmed: 28805820
Nat Med. 2013 Nov;19(11):1423-37
pubmed: 24202395
Cancer Discov. 2018 Apr;8(4):458-477
pubmed: 29386193
Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7124-9
pubmed: 27274052
Mol Cell Proteomics. 2008 Sep;7(9):1598-608
pubmed: 18463090
BMC Cancer. 2015 Nov 02;15:833
pubmed: 26525741
Mol Cell. 2015 Jun 18;58(6):1028-39
pubmed: 25982114
Nat Commun. 2015 Oct 27;6:8746
pubmed: 26503059
Nat Genet. 2015 Apr;47(4):320-9
pubmed: 25706628
J Clin Invest. 2014 Dec;124(12):5291-304
pubmed: 25384218
Mol Cancer Ther. 2019 Jul;18(7):1302-1311
pubmed: 31064868
Ann Surg Oncol. 2000 Mar;7(2):133-8
pubmed: 10761792
Oncol Rep. 2006 Jun;15(6):1445-51
pubmed: 16685378
Cancer Cell. 2012 Nov 13;22(5):571-84
pubmed: 23153532
Mol Cell. 2018 Aug 16;71(4):592-605.e4
pubmed: 30057199
Nat Rev Cancer. 2020 Mar;20(3):174-186
pubmed: 31980749
Nature. 2010 Dec 23;468(7327):1067-73
pubmed: 20871596
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Mol Cell. 2013 Mar 7;49(5):843-57
pubmed: 23317504
Bioinformatics. 2015 Jul 15;31(14):2382-3
pubmed: 25765347
J Surg Oncol. 2003 Aug;83(4):222-6
pubmed: 12884234
ACS Chem Biol. 2015 Aug 21;10(8):1770-7
pubmed: 26035625
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Cell. 2013 Dec 19;155(7):1581-1595
pubmed: 24360279
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8758-63
pubmed: 12840145
Nat Med. 2017 Sep;23(9):1046-1054
pubmed: 28805821
Science. 2015 Jun 19;348(6241):1376-81
pubmed: 25999370
Nat Rev Drug Discov. 2014 May;13(5):337-56
pubmed: 24751816
Cancer Cell. 2020 Sep 14;38(3):412-423.e9
pubmed: 32679107
Science. 2018 May 18;360(6390):800-805
pubmed: 29622725