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P65 Promotes DNMT-1 Recruitment to Chromatin and Represses Transcription of the Tumor Metastasis Suppressor Gene BRMS1

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P65 Promotes DNMT-1 Recruitment to Chromatin and Represses Transcription of the Tumor Metastasis Suppressor Gene BRMS1 Oncogene (2012) 31, 1143–1154 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc ORIGINAL ARTICLE Phosphorylation of RelA/p65 promotes DNMT-1 recruitment to chromatin and represses transcription of the tumor metastasis suppressor gene BRMS1 Y Liu1, MW Mayo2, AS Nagji1, PW Smith1, CS Ramsey2,DLi2 and DR Jones1 1Department of Surgery, University of Virginia, Charlottesville, VA, USA and 2Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA The majority of patients with lung cancer present with Introduction metastatic disease. Chronic inflammation and subsequent activation of nuclear factor-jB (NF-jB) have been Nuclear factor-kB (NF-kB) is aberrantly activated in associated with the development of cancers. The RelA/ malignancies and its activation is essential for tumor p65 subunit of NF-jB is typically associated with proliferation and metastatic process (Bours et al., 1994; transcriptional activation. In this report we show that Baldwin, 1996; Helbig et al., 2003; Bobrovnikova- RelA/p65 can function as an active transcriptional Marjon et al., 2004; Denlinger et al., 2004; Huber repressor through enhanced methylation of the BRMS1 et al., 2004; Karin and Greten, 2005; Takada et al., (breast cancer metastasis suppressor 1) metastasis sup- 2005). Typically, NF-kB is a transcriptional activator pressor gene promoter via direct recruitment of DNMT-1 after stimulation with proinflammatory cytokines, such (DNA (cytosine-5)-methyltransferase 1) to chromatin in as tumor necrosis factor (TNF) and interleukin-1 response to tumor necrosis factor (TNF). TNF-mediated (IL-1) (Chen et al., 1998; Mayo and Baldwin, 2000). phosphorylation of S276 on RelA/p65 is required for In unstimulated cell nuclei, RelA/p65 and/or p50 RelA/p65–DNMT-1 interactions, chromatin loading of are transcriptionally repressed through interactions on DNMT-1 and subsequent BRMS1 promoter methylation chromatin with histone deacetylases 1 and 3 corepressor and transcriptional repression. The ability of RelA/p65 to complexes. Following stimulation, derepression of function as an active transcriptional repressor is promoter RelA/p65 occurs through phosphorylation on serines specific, as the NF-jB-regulated gene cIAP2 (cellular 276 (Zhong et al., 2002; Dong et al., 2008) or 536 inhibitor of apoptosis 2) is transcriptionally activated (Hoberg et al., 2006) that enhances its association with whereas BRMS1 is repressed under identical conditions. histone acetyltransferases (HATs), allowing RelA/p65 Small-molecule inhibition of either of the minimal to activate transcription (Chen et al., 1998, 2005). interacting domains between RelA/p65–DNMT-1 and In 2004, Campbell first described the ability of RelA/ RelA/p65–BRMS1 promoter abrogates BRMS1 methy- p65 to function as an ‘active repressor’ under specific lation and its transcriptional repression. The ability of cytotoxic stimuli (Campbell et al., 2004). Interestingly, RelA/p65 to directly recruit DNMT-1 to chromatin, TNF and IL-6, both classical stimuli for NF-kB resulting in promoter-specific methylation and transcrip- activation, have also been correlated with enhanced tional repression of tumor metastasis suppressor gene methylation of promoter CpG island (CGI), resulting in BRMS1, highlights a new mechanism through which transcriptional repression of tumor-suppressor genes NF-jB can regulate metastatic disease, and offers (Hodge et al., 2005; Ushijima and Okochi-Takada, a potential target for newer-generation epigenetic 2005; Wehbe et al., 2006). These observations suggest oncopharmaceuticals. that under specific conditions, NF-kB activation may Oncogene (2012) 31, 1143–1154; doi:10.1038/onc.2011.308; be related to methylation of specific genes, although the published online 18 July 2011 mechanisms through which this occurs are unknown. BRMS1 (breast cancer metastasis suppressor 1) was Keywords: DNMT-1; phosphorylation; RelA/p65; originally identified as a tumor metastasis suppressor, TNF; transcription and its expression levels have been shown to be markedly reduced in various cancers (Meehan and Welch, 2003; Liu et al., 2006b); with the loss of the BRMS1 allele coinciding with increased numbers of metastases and decreased survival in breast cancer and lung cancer patients (Hicks et al., 2006; Zhang et al., 2006; Smith et al., 2009). We have shown Correspondence: Dr DR Jones, Department of Surgery, University of that methylation of the specific CGI (À531 to þ 608) Virginia, Box 800679, Charlottesville, VA 22908-0679, USA. contributes to BRMS1 transcriptional repression in E-mail: [email protected] Received 21 February 2011; revised 6 June 2011; accepted 15 June 2011; non-small-cell lung cancer (NSCLC) cells and human published online 18 July 2011 tumors (Nagji et al., 2010). RelA/p65 mediates promoter-specific methylation YLiuet al 1144 In this report we provide evidence that RelA/p65 whether TNF promotes lung cancer cell invasion functions as an active transcriptional repressor through through regulation of BRMS1 expression. We observed enhanced methylation of the BRMS1 promoter via that TNF reduced both protein (Figure 1b) and direct recruitment of DNMT-1 (DNA (cytosine-5)- transcription (Figure 1c) levels of BRMS1 in a time- methyltransferase 1) to chromatin in response to TNF. dependent manner in NSCLC H157 and H1299 cells, Our study offers new insight into an alternative and normal bronchial epithelial cells, respectively. These mechanism through which NF-kB can function as data suggest that repression of BRMS1 transcription is a an active transcriptional repressor to promote tumor plausible mechanism through which inflammatory metastasis. cytokines promote the metastatic potential of NSCLC. Given that methylation of the CGI results in BRMS1 transcriptional repression (Nagji et al., 2010), we Results hypothesized that TNF may be decreasing BRMS1 transcription through enhanced BRMS1 promoter TNF represses BRMS1 transcription via BRMS1 methylation. As we expected, TNF increased BRMS1 promoter methylation methylation in a time- and dose-dependent manner Chronic inflammation and the proinflammatory cyto- in normal bronchial epithelial cells (Figure 1d and kines are increasingly appreciated as contributing Supplementary Figure S2A). These results establish that significantly to cancer progression (Coussens and TNF enhances BRMS1 transcriptional repression Werb, 2002; Greten and Karin, 2004; Pikarsky et al., through DNA methylation. 2004; Karin and Greten, 2005). In our model system the proinflammatory cytokine TNF significantly increased RelA/p65 mediates TNF-induced methylation and the invasive potential of NSCLC H157 and H1299 cells transcriptional repression of BRMS1 (Figure 1a). Similarly, small interfering RNA knock- The biological functions of TNF are realized primarily down of endogenous BRMS1 resulted in a dramatic by activating NF-kB, particularly its active subunit increase in the invasive potential of NSCLC cells RelA/p65 (Greten et al., 2004). To examine the (Supplementary Figure S1). requirement of endogenous RelA/p65 for enhancing As we have shown that BRMS1 is downregulated in BRMS1 promoter methylation following TNF treat- NSCLC (Liu et al., 2006b), we next sought to determine ment, p65WT and p65À/À mouse embryo fibroblast cells Figure 1 TNF reduces BRMS1 expression. (a) TNF promotes lung cancer cells invasion. NSCLC cells were treated with TNF (40 ng/ml) for 48 h and the invasion capability was quantified using Boyden chamber assays. Bar graphs show average cell counts per field. Data are presented as mean±s.d. *Po0.01 and **Po0.001 compared with No add. (b) TNF reduces BRMS1 protein level. NSCLC cells were treated with TNF (40 ng/ml) at the indicated time points. The protein levels of BRMS1 were evaluated by western blots. (c) TNF inhibits BRMS1 transcription. Normal bronchial epithelial (NHBE) cells were treated with TNF (40 ng/ml), and mRNA of endogenous BRMS1 was detected by quantitative reverse transcription–PCR (RT–PCR) at the indicated time points (0, 1, 2, 4, 8 and 16 h). (d) TNF induces methylation of the BRMS1 promoter. NHBE cells were treated with TNF as described in (c) and the relative methylation status of BRMS1 was evaluated by quantitative methylation-specific PCR (MSP). Oncogene RelA/p65 mediates promoter-specific methylation YLiuet al 1145 Figure 2 RelA/p65 mediates TNF-induced BRMS1 transcriptional repression via methylation. (a) RelA/p65 mediates TNF-induced methylation. p65WT and p65À/À mouse embryo fibroblasts (MEFs) were treated with 5-Aza (5 mM) for 5 days followed by stimulation with TNF (20 ng/ml). The relative methylation of BRMS1 was detected by quantitative methylation-specific PCR (MSP). The data are plotted as the fold over No add group, where results from the group of No add were normalized to 1 for p65WT MEFs. *Po0.05 compared with the same time point in p65WT control group. (b) RelA/p65 is required for TNF-induced BRMS1 transcriptional repression. p65WT and p65À/À MEFs were treated with 5-Aza and TNF in the same pattern as described in (a). The mRNA of BRMS1 was analyzed by quantitative reverse transcription–PCR (RT–PCR). *Po0.05 compared with the same time point in p65WT control group. (c) RelA/p65 mediates methylation of the BRMS1 promoter in NSCLC. H157 V/I cells were treated with 5-Aza (5 mM)as described previously. Relative methylation of BRMS1 promoter was determined by quantitative MSP at the indicated time point. *Po0.05 and **Po0.01 compared with the same time point in H157I; wPo0.05 compared with
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