title: 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.
abstract: 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.
authors.affiliation: Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Physiology, University of Ghent, K. L. Ledeganckstraat 35, Ghent, Belgium.
authors.forename: 'Matladi N
authors.initials: MN
authors.lastname: Ndlovu
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.forename: Karlien
authors.initials: K
authors.lastname: Van Wesemael
authors.forename: Pieter
authors.initials: P
authors.lastname: Callebert
authors.forename: Dany
authors.initials: D
authors.lastname: Chalbos
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.forename: Wim
authors.initials: W
authors.lastname: Vanden Berghe
mesh_terms: 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
chemical_list: 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
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