The International Journal of Biochemistry & Cell Biology 55 (2014) 220–226 Contents lists available at ScienceDirect The International Journal of Biochemistry & Cell Biology jo u r n al homep ag e: www.elsevier.com/locate/biocel Short communication Chromatin remodeling protein SMAR1 regulates NF-B dependent Interleukin-8 transcription in breast cancer Sunil K. Malonia a,1 , Bhawna Yadav a,3 , Surajit Sinha a,2,3 , Gwendel Lazennec b , Samit Chattopadhyay a,∗ a National Centre for Cell Science, Ganeshkhind, Pune 411007, India b INSERM, U844, University of Montpellier, Montpellier F-34091, France a r t i c l e i n f o Article history: Received 8 May 2014 Received in revised form 14 August 2014 Accepted 8 September 2014 Available online 18 September 2014 Keywords: SMAR1 NF-B HDAC1 Transcription Repressor a b s t r a c t Interleukin-8 (IL-8) is a pleiotropic chemokine involved in metastasis and angiogenesis of breast tumors. The expression of IL-8 is deregulated in metastatic breast carcinomas owing to aberrant NF-B activity, which is known to positively regulate IL-8 transcription. Earlier, we have shown that tumor suppressor SMAR1 suppresses NF-B transcriptional activity by modulating IB function. Here, we show that NF-B target gene IL-8, is a direct transcriptional target of SMAR1. Using chromatin immunoprecipitation and reporter assays, we demonstrate that SMAR1 binds to IL-8 promoter MAR (matrix attachment region) and recruits HDAC1 dependent co-repressor complex. Further, we also show that SMAR1 antagonizes p300- mediated acetylation of RelA/p65, a post-translational modification indispensable for IL-8 transactivation. Thus, we decipher a new role of SMAR1 in NF-B dependent transcriptional regulation of pro-angiogenic chemokine IL-8. © 2014 Elsevier Ltd. All rights reserved. 1. Introduction Interleukin-8 (IL-8) is a pleiotropic chemokine involved in vari- ety of pathophysiological processes. It has been shown to play an important role in human cancers by modulating metastasis and angiogenesis (Xie, 2001; Ali and Lazennec, 2007). A wealth of evidence suggests that IL-8 is aberrantly expressed in num- ber of cancers including breast cancer (Freund et al., 2003; Yao et al., 2007). An increased serum IL-8 level has been reported in metastatic breast cancers, which correlates with early dissemi- nation and survival (Benoy et al., 2004). The highly metastatic breast carcinoma cells lacking estrogen receptor-, produce more IL-8 and the expression of this chemokine is differentially reg- ulated in metastatic and non-metastatic breast cancer cells (De Larco et al., 2001; Freund et al., 2004). This is partially attributed to the differential function of inducible transcription factors, which govern IL-8 transcription (Hoffmann et al., 2002). NF-B ∗ Corresponding author at: National Centre for Cell Science, Ganeshkhind, Pune 411007, India. Tel.: +91 20 25708064. E-mail address: samit@nccs.res.in (S. Chattopadhyay). 1 Present address: University of Massachusetts Medical School, Worcester, MA, USA. 2 Present address: Memorial Sloan Kettering Cancer Institute, New York, USA. 3 These authors contributed equally to this work. transcription factors play a major role in constitutive expression of IL-8 in metastatic breast cancer cells (Freund et al., 2004). Activity of NF-B is itself regulated by several important post-translational modifications, which dictate stimulus dependent and independent regulation of its target genes. A number of post-translational mod- ifications such as phosphorylation, ubiquitination or acetylation of RelA/p65 has been documented (Perkins, 2006; Oeckinghaus and Ghosh, 2009). Acetylation of RelA/p65 is the most impor- tant post-translational modification required for its transactivation function and this is achieved by its interaction with co-activators such as CBP (CREB-binding protein)/p300 (Zhong et al., 2002). On the other hand, deacetylation of RelA/p65 by different histone deacetylases (HDACs) such as HDAC3 and SIRT1 is also reported to modulate its transactivation potential (Chen and Greene, 2004; Yeung et al., 2004). Therefore, the acetylation and deacetylation switch governs the activator or repressor function of RelA/p65. The proteins that can modulate acetylation and deacetylation dynam- ics of RelA/p65, play a pivotal role in regulation of its target genes. We previously identified a subset of NF-B target genes, the expression of which altered upon knockdown and overexpress- ion of SMAR1 (Singh et al., 2009). One such candidate gene was Interleukin-8 (IL-8), a bonafide NF-B target gene. In this report, we elaborate on molecular mechanisms that confer differential expres- sion/regulation of IL-8 in metastatic and non-metastatic breast http://dx.doi.org/10.1016/j.biocel.2014.09.008 1357-2725/© 2014 Elsevier Ltd. All rights reserved.