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.

Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain

“…Another group of TFs identified in our study provide novel avenues for exploration. For instance, TFAP2C expression was significantly associated with lung relapses, consistent with a recent study [27]. TFAP2C is a pioneer factor that plays important roles in pluripotency and lineage differentiation [87,88].…”

“…Moreover, the technique used in this study, omni-ATAC-seq, has been shown to have the same robustness for TF binding prediction as the previous gold standard DNAase-seq [85]. Our pipeline uncovered robust candidate epigenetic markers of relapse that were not identified by previous reports using ChIP-Seq only [27]. These TFs may help establish or maintain chromatin states which are permissive for the expression of prometastatic gene expression programs.…”

“…It has yet to be determined if particular chromatin alterations can independently explain the metastatic competence or organotropism of breast cancer cells. Furthermore, previous studies have predicted enhancerdriven gene expression changes using a nearest gene approach, whereas experimental techniques like HiChIP enables a more robust way of identifying enhancer-gene links [27,28]. Also, the transcription factors linked to particular chromatin landscapes and their association with lung or brain metastasis gene expression remain underexplored.…”

Super enhancers—Functional cores under the 3D genome

“…Young and colleagues found that H3 lysine 27 acetylation (H3K27ac) is the label for super ehnancers, 34,35 which makes chromatin structures looser, providing ideal sites for active transcription machine. In addition, master transcription factors tend to co-bind at the SEs ( Figure 1A).…”

MiR-524-5p Suppresses Migration, Invasion, and EMT Progression in Breast Cancer Cells Through TargetingFSTL1

“…2,3 However, for patients with advanced BC, the efficacies of surgery and chemotherapy are low due to distant metastasis of cancer. 4 Distant metastasis is an important factor contributing to BC development, [5][6][7] and many BC patients have metastatic BC at the time of diagnosis, and their 5-year survival rates are only *27%. 8 Similar to other cancers, the occurrence, development, and metastasis of BC are closely related to the abnormal expressions of multiple genes such as oncogenes, tumor-suppressor and metastasisrelated genes.…”