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Molecular and Cellular Biology, October 2009, p. 5488-5504, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.01657-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

'Matladi N. Ndlovu,1,{dagger} Carine Van Lint,2 Karlien Van Wesemael,1 Pieter Callebert,1 Dany Chalbos,3 Guy Haegeman,1 and Wim Vanden Berghe1*

Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Physiology, University of Ghent, K. L. Ledeganckstraat 35, Ghent, Belgium,1 Laboratoire de Virologie Moléculaire, Institut de Biologie et de Medecine Moleculaires, Université Libre de Bruxelles, Rue des Profs Jeener et Brachet 12, 6041 Gosselies, Belgium,2 IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U896, Université Montpellier, CRLC Val d'Aurelle, Montpellier F-34298, France3

Received 24 October 2008/ Returned for modification 1 December 2008/ Accepted 5 August 2009

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-{kappa}B 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-{kappa}B 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-{kappa}B 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-{kappa}B and AP-1 Fra-1 transcription factors and silencing of IL-6 promoter chromatin accessibility.

* Corresponding author. Mailing address: Laboratory of Eukaryotic Gene Expression and Signal Transduction, Department of Physiology, University of Ghent, K. L. Ledeganckstraat 35, Ghent, Belgium. Phone: 32 9 2645147. Fax: 32 9 92645304. E-mail: w.vandenberghe{at}ugent.be

{triangledown} Published ahead of print on 17 August 2009.

{dagger} Present address: Laboratory of Cancer Epigenetics, Free University of Brussels, Faculty of Medicine, 808 route de Lennik, 1070 Brussels, Belgium.

Molecular and Cellular Biology, October 2009, p. 5488-5504, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.01657-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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