Triple-negative breast cancers (TNBC) lack the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). TNBC is the most aggressive breast cancer subtype and is often associated with distant metastasis, poor prognosis, and lack of targeted treatment options. The failure to identify a few genes driving metastasis through sequencing of paired tumors at primary and metastatic sites implies that epigenetic mechanisms may play important roles in TNBC metastasis. Recently, we found that an epigenetic enzyme coactivator associated arginine methyltransferase 1 (CARM1) is highly expressed in TNBC and its high expression correlates with poor prognosis. Subsequently we identified BRG1-Associated Factor 155 (BAF155), a component of SWI/SNF chromatin remodeling complex, as a novel CARM1 substrate. Transcriptome analyses of BAF155 methylation competent and defective cell lines identified many genes involved in regulating cancer metastasis are methyl-BAF155 targets. Methylation of BAF155 was found to promote metastasis in the TNBC xenografted mouse models. We generated a methyl-BAF155 antibody that could specifically detect methylated BAF155 (me-BAF155) by IHC and chromatin immunoprecipitation followed by sequencing (ChIP-seq). We mapped global me-BAF155 genomic association sites using ChIP-seq and discovered that me-BAF155 was highly enriched in super-enhancers (SEs), regulatory elements on chromatin that are known to drive high transcription of many oncogenes. SEs are known to recruit BRD4, a BET family bromodomain protein. Indeed, global me-BAF155 binding peaks greatly overlap with those of BRD4 binding sites. Treatment of TNBC cells with either BRD4 inhibitor JQ1 or CARM1 inhibitor TP-064 significantly reduced the expression of me-BAF155 target genes. Together our data suggest that me-BAF155 is an important epigenetic target for treatment of cancer metastasis in TNBC cells.
Citation Format: Eui-Jun Kim, Yidan Wang, Li Lu, Lixin Rui, Xuehua Zhong, Kari B. Wisinski, Wei Xu. Methylated BAF155 promotes cancer metastasis by cooperating with BRD4 to potentiate genes addicted to super-enhancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4313.