Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells.
Interleukin-6 (IL-6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, metastasis, and subversion of immunity, and changes the response to hormones and to chemotherapeutics. We explored transcription mechanisms involved in differential IL-6 gene expression in breast cancer cells with different metastatic properties. In weakly metastatic MCF7 cells, histone H3 K9 methylation, HP1 binding, and weak recruitment of AP-1 Fra-1/c-Jun, NF-kappaB p65 transcription factors, and coactivators is indicative of low chromatin accessibility and gene transcription at the IL-6 gene promoter. In highly metastatic MDA-MB231 cells, strong DNase, MNase, and restriction enzyme accessibility, as well potent constitutive transcription of the IL-6 gene promoter, coincide with increased H3 S10 K14 phosphoacetylation and promoter enrichment of AP-1 Fra-1/c-Jun and NF-kappaB p65 transcription factors and MSK1, CBP/p300, Brg1, and Ezh2 cofactors. Complementation, silencing, and kinase inhibitor experiments further demonstrate involvement of AP-1 Fra-1/c-Jun and NF-kappaB p65/RelB members, but not of the alpha estrogen receptor in promoting chromatin accessibility and transcription across the IL-6 gene promoter in metastatic breast cancer cells. Finally, the natural withanolide Withaferin A was found to repress IL-6 gene transcription in metastatic breast cancer cells upon dual inhibition of NF-kappaB and AP-1 Fra-1 transcription factors and silencing of IL-6 promoter chromatin accessibility.
Ndlovu
'Matladi N
MN
Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Physiology, University of Ghent, K. L. Ledeganckstraat 35, Ghent, Belgium.
Van Lint
Carine
C
Van Wesemael
Karlien
K
Callebert
Pieter
P
Chalbos
Dany
D
Haegeman
Guy
G
Vanden Berghe
Wim
W
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D004875:Ergosterol / Q000031:analogs & derivatives / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054358:Withanolides; D000099169:Fos-Related Antigen 1
D002843:Chromatin; D004875:Ergosterol; D006657:Histones; D015850:Interleukin-6; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D054358:Withanolides; D000099169:Fos-Related Antigen 1; C009684:withaferin A
Cell. 2007 Feb 23;128(4):693-705
17320507
EMBO Rep. 2004 May;5(5):490-6
15105826
Cancer Res. 2000 Jul 1;60(13):3359-63
10910038
Mol Cell Biol. 2008 Jul;28(13):4407-23
18443042
EMBO J. 2007 Jan 24;26(2):412-23
17245431
Nucleic Acids Res. 2008 May;36(8):2639-53
18344520
Biochem Pharmacol. 2004 Sep 15;68(6):1171-85
15313415
Science. 1998 Mar 27;279(5359):2118-21
9516115
Mol Cancer Ther. 2006 Jun;5(6):1434-45
16818501
Oncogene. 2004 Aug 12;23(36):6105-14
15208657
Mol Cell Biol. 2007 Apr;27(8):2870-85
17283044
J Immunol. 2007 Apr 15;178(8):5048-57
17404287
Oncogene. 2004 Mar 18;23(12):2138-45
14676835
Cancer Res. 2006 May 1;66(9):4852-62
16651441
Genes Dev. 2006 Feb 1;20(3):282-96
16452502
Cancer Res. 2007 Dec 15;67(24):11742-50
18089804
J Clin Invest. 2007 May;117(5):1175-83
17476347
Mini Rev Med Chem. 2008 Jun;8(7):677-88
18537723
Semin Cancer Biol. 2007 Oct;17(5):363-9
17555985
Mol Cell Biol. 2007 Jul;27(14):5105-19
17502350
Nature. 2002 Jan 31;415(6871):530-6
11823860
J Biol Chem. 2007 Feb 16;282(7):4253-4264
17150968
Immunity. 2005 Jul;23(1):89-99
16039582
Nat Cell Biol. 2006 Apr;8(4):407-15
16531993
Nature. 2005 Dec 22;438(7071):1116-22
16222246
Genes Dev. 2008 May 1;22(9):1159-73
18408078
Biochem Biophys Res Commun. 1999 May 19;258(3):644-7
10329438
Nat Genet. 2004 Aug;36(8):900-5
15247917
EMBO J. 2006 Oct 18;25(20):4843-53
17036053
Cell. 2008 Jul 11;134(1):85-96
18614013
J Biol Chem. 2007 Nov 9;282(45):33210-7
17766920
Genes Dev. 2006 Jun 1;20(11):1405-28
16751179
Nat Rev Cancer. 2003 Oct;3(10):768-80
14570043
Cancer Res. 2005 Mar 15;65(6):2170-8
15781628
Am J Pathol. 2005 Apr;166(4):1187-203
15793298
J Biol Chem. 1998 Feb 6;273(6):3285-90
9452444
Curr Med Chem. 2006;13(8):935-58
16611076
Cell. 2007 Sep 21;130(6):1083-94
17825402
J Biol Chem. 2005 Feb 18;280(7):5178-87
15563468
Nucleic Acids Res. 1999 Nov 15;27(22):4483-90
10536159
EMBO J. 1997 Apr 15;16(8):2072-85
9155033
Cancer Res. 2006 May 1;66(9):4610-6
16651411
BMC Cancer. 2007 Apr 03;7:59
17407600
Nature. 2007 Apr 5;446(7136):690-4
17377533
EMBO J. 1993 Oct;12(10):3879-91
8404856
Bioessays. 2007 Sep;29(9):842-5
17688287
J Virol. 1991 Dec;65(12):6790-9
1942252
Lancet. 2005 Feb 19-25;365(9460):671-9
15721472
J Biol Chem. 1999 Nov 5;274(45):32091-8
10542243
Oncogene. 2000 Jul 6;19(29):3235-44
10918580
Planta Med. 2008 Oct;74(13):1593-601
18704881
Biochem Pharmacol. 2006 Oct 30;72(9):1114-31
16934762
Mol Cell Biol. 2008 Feb;28(3):926-38
18025106
Mol Cell. 2007 Oct 26;28(2):200-13
17964260
Nat Rev Cancer. 2003 Nov;3(11):859-68
14668816
Nature. 2008 Jul 24;454(7203):436-44
18650914
J Virol. 1994 Apr;68(4):2632-48
8139041
Exp Cell Res. 2008 Jul 1;314(11-12):2187-98
18508047
Mol Cell Biol. 2004 Jul;24(14):6488-500
15226448
Nucleic Acids Res. 2005 Jan 12;33(1):225-34
15647505
Cell. 2008 Mar 7;132(5):887-98
18329373
Genes Dev. 2007 Jul 15;21(14):1714-9
17639077
Nat Genet. 2007 Mar;39(3):311-8
17277777
Mol Cell. 2006 Nov 3;24(3):367-81
17081988
Genome Res. 2008 Jul;18(7):1084-91
18448704
Curr Opin Cell Biol. 2008 Apr;20(2):201-7
18291635
Science. 2005 Oct 14;310(5746):306-10
16224021
Cancer Cell. 2006 Dec;10(6):515-27
17157791
Mol Cell Biol. 2004 Sep;24(18):7914-30
15340054
Am J Pathol. 2007 Feb;170(2):787-8; author reply 788-9
17255344
EMBO J. 2006 Feb 22;25(4):798-810
16467852
Curr Opin Genet Dev. 2006 Feb;16(1):65-70
16377173
Cancer Res. 2003 May 1;63(9):2206-15
12727841
EMBO J. 1993 Aug;12(8):3249-59
8344262
Cancer Res. 2008 Sep 15;68(18):7661-9
18794155
J Biol Chem. 2001 Jan 26;276(4):2852-7
11053448
Mol Cell Biol. 2004 Sep;24(17):7806-19
15314185
Breast Cancer Res Treat. 2005 Oct;93(3):237-46
16172796
Nat Rev Genet. 2007 Apr;8(4):286-98
17339880
Cancer Res. 2007 Jan 1;67(1):246-53
17185378
Immunity. 2009 Mar 20;30(3):372-83
19285436
Nat Rev Genet. 2009 Mar;10(3):161-72
19204718
Nat Biotechnol. 2007 Feb;25(2):244-8
17220878
Nat Immunol. 2005 May;6(5):439-45
15843800
J Exp Med. 2003 Feb 17;197(4):413-23
12591900
Cell Signal. 2008 Aug;20(8):1489-96
18502099
Oncogene. 2005 Feb 17;24(8):1434-44
15608675
Int J Biochem Cell Biol. 2009 Jan;41(1):176-84
18793748
J Biol Chem. 2004 Oct 8;279(41):42374-82
15269206
EMBO J. 2003 Mar 17;22(6):1313-24
12628924
Nat Cell Biol. 2007 Apr;9(4):470-8
17369819
Development. 2006 Jan;133(2):229-35
16339185
Carcinogenesis. 2006 Feb;27(2):344-9
16267097
Altern Med Rev. 2006 Dec;11(4):269-77
17176166