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

Kening Li,Yuxin Du,Aman‐Chandra Kaushik,Dong‐Qing Wei,Muhammad Junaid,Congling Xu

doi:10.1111/jcmm.14424

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.

Highlights

With increasing incidence and mortality, breast cancer is one of the most common malignancy and the leading cause of death for women worldwide.[1]
Results showed that 69.3% (1941/2802) differentially expressed genes (DEGs) were associated with the histone modification changes (Table 1), indicat‐ ing the important role of chromatin reprogramming in regulating gene expression in lung metastasis of breast cancer
It was shown that the migration ability was strikingly inhibited in LMO4 decreased cells (Figure 7E). These results suggested that LMO4 played an essential role in reg‐ ulating cell migration and epithelial‐mesenchymal transition (EMT) in lung metastasis of breast cancer

Summary

| INTRODUCTION

With increasing incidence and mortality, breast cancer is one of the most common malignancy and the leading cause of death for women worldwide.[1]. Computational analysis of global histone modification profiles could provide a complete picture of chromatin structure in specific cells, and facilitate the prediction of active cis‐elements and transcription regulatory network. MDA‐MB‐231 and LM2‐4175 cell lines are the major model for analysing lung metastasis of TNBC.[13]. Signature of lung metastasis was iden‐ tified using transcription data of MDA‐MB‐231 and LM2‐4175.13 the changes of chromatin structure of whole genome and the specific regulatory network during lung metastasis of breast cancer were still poorly understood. We analysed the chromatin remodelling and tran‐ scriptional changes during lung metastasis of breast cancer by in‐ tegrating ChIP‐Seq data of multiple histone modifications and RNA‐Seq data. Our study provided a comprehensive insight into the whole cistrome in the lung‐meta‐ static breast cancer cells, as well as data resource for the develop‐ ment of therapeutic strategies based on epigenetics

| MATERIALS AND METHODS

| DISCUSSION

Findings

CONFLICT OF INTEREST