Approximately 30% of all driver genes identified in cancer are related to chromatin structure and function. Distinct from common mechanisms involving altered expression or mutations of epigenetic modifiers, we identified post-translational modification of a chromatin regulator dependent mechanism for cancer progression and metastasis. BAF155, a component of SWI/SNF chromatin remodeling complex, is methylated by arginine methyltransferase CARM1 at a single site, R1064. Using methyl-BAF155 (me- BAF155) specific antibody for ChIP-seq, we found that me-BAF155 binding peaks are enriched with high- density H3K27Ac and H3K4me1 that feature the super-enhancers (SEs). SEs are important regulatory elements controlling oncogene expression in cancer cells. Because SEs recruit bromodomain containing protein BRD4, the expression levels of oncogenes are often sensitive to the BRD4 inhibitor JQ1. We showed that both JQ1 and CARM1 inhibitor treatment blocked the expression of me-BAF155 target genes and the recruitment of me-BAF155 and BRD4 to candidate genes in breast cancer cells. This leads to the hypothesis that me-BAF155 regulates oncogenes addicted to SEs thus promoting cancer metastasis.
Aim 1 will examine the global me-BAF155 chromatin association upon treatment with JQ1 and CARM1 inhibitors. Because JQ1 is under clinical investigation for treatment of various cancer types, the novel mechanism of gene regulation via SEs in me-BAF155 driven cancer would suggest new therapeutic means to treat breast cancers with high levels of me-BAF155. We will test our hypothesis using different cell lines and patient- derived xenograft models. Furthermore, integration of microarray and me-BAF155 ChIP-seq data identifies key genes in the Hippo pathway dependent on BAF155 methylation. Therefore, our second hypothesis being tested (Aim 2) is that YAP activity potentiated by me-BAF155 contributes to cell growth, invasion and metastasis. Collectively, our study will validate the functional significance of me-BAF155 in driving cancer metastasis in different pre-clinical models and provide mechanistic insights into the oncogenic functions of me-BAF155. Epigenetic therapy has not been widely used for breast cancer treatment due to the lack of defined target and specific inhibitors for epigenetic enzymes. Our studies will lay solid foundation for the application of epigenetic drugs (e.g. CARM1 inhibitor) that target BAF155 methylation reaction in preventing and treating breast cancer metastasis.
Breast cancer causes leading cancer related death in U.S. women. We recently showed that methylation of BAF155 by CARM1 promotes breast cancer cell migration and metastasis. This study focuses on dissecting functions of me-BAF155 using genomic approaches and inhibiting BAF155 methylation using novel epigenetic drugs. The study will provide mechanistic insights into how BAF155 gains oncogenic functions and facilitate rationale design of epigenetic drugs for cancer treatment.
