Comprehensive epigenetic analyses reveal master regulators driving lung metastasis of breast cancer

Abstract

The lung metastasis of breast cancer involves complicated regulatory changes driven by chromatin remodelling. However, the epigenetic reprogramming and regulatory mechanisms in lung metastasis of breast cancer remain unclear. Here, we generated and analysed genome-wide profiles of multiple histone modifications (H3K4me3, H3K27ac, H3K27me3, H3K4me1 and H3K9me3), as well as transcriptome data in lung-metastatic and non-lung-metastatic breast cancer cells. Our results showed that the expression changes were correlated with the enrichment of specific histone modifications in promoters and enhancers. Promoter and enhancer reprogramming regulated gene expression in a synergetic way, and involved in multiple important biological processes and pathways. In addition, lots of gained super-enhancers were identified in lung-metastatic cells. We also identified master regulators driving differential gene expression during lung metastasis of breast cancer. We found that the cooperations between regulators were much closer in lung-metastatic cells. Moreover, regulators such as TFAP2C, GTF2I and LMO4 were found to have potential prognostic value for lung metastasis free (LMF) survival of breast cancer. Functional studies motivated by our data analyses uncovered an important role of LMO4 in regulating metastasis. This study provided comprehensive insights into regulatory mechanisms, as well as potential prognostic markers for lung metastasis of breast cancer.