Sorafenib Inhibits Epithelial-Mesenchymal Transition through an Epigenetic-Based Mechanism in Human Lung Epithelial Cells

Juyong Zhang,Fei Gao,Yi Liu,Zhaowei Gao,Yue-Lei Chen,Xiaoyan Ding,Guanyu Ji,Weiying Fang,Jun Wang,Arun Rishi

doi:10.1371/journal.pone.0064954

Abstract

The epithelial to mesenchymal transition (EMT) has been well recognized for many decades as an essential early step in the progression of primary tumors towards metastases. Widespread epigenetic reprogramming of DNA and histone modifications tightly regulates gene expression and cellular activity during carcinogenesis, and epigenetic therapy has been developed to design efficient strategies for cancer treatment. As the first oral agent approved for the clinical treatment of cancer, sorafenib has significant inhibitory effects on tumor growth and EMT. However, a detailed understanding of the underlying epigenetic mechanism remains elusive. In this manuscript, we performed a ChIP-seq assay to evaluate the activity of sorafenib on the genome-wide profiling of histone modifications. We demonstrate that sorafenib largely reverses the changes in histone modifications that occur during EMT in A549 alveolar epithelial cells. Sorafenib also significantly reduces the coordinated epigenetic switching of critical EMT-associated genes in accordance with their expression levels. Furthermore, we show that sorafenib potentiates histone acetylation by regulating the expression levels of histone-modifying enzymes. Collectively, these findings provide the first evidence that sorafenib inhibits the EMT process through an epigenetic mechanism, which holds enormous promise for identifying novel epigenetic candidate diagnostic markers and drug targets for the treatment of human malignancies.

Highlights

As one of the most common types of human diseases, cancer is the third leading cause of mortality in China and worldwide for both men and women, and more than 90% of deaths from cancer are due to the metastatic spread of primary tumors [1]
These data indicate that sorafenib counteracts TGF-b1-induced epithelial-mesenchymal transition (EMT) and cell migration in A549 adenocarcinoma epithelial cells and provide a possible explanation for its effects with regard to tumor control and reduced cancer metastasis
By crossmatching the differential histone modification regions (DHMRs) identified between control and TGF-b1treated cells with those between control and TGF-b1+sorafenibtreated cells, we found that 44%–72% of the DHMRs between control and TGF-b1-treated cells disappeared in the TGFb1+sorafenib-treated cells (Figure 2C)

Summary

Introduction

As one of the most common types of human diseases, cancer is the third leading cause of mortality in China and worldwide for both men and women, and more than 90% of deaths from cancer are due to the metastatic spread of primary tumors [1]. The breakdown of epithelium homeostasis, which leads to aggressive cancer progression, corresponds with the loss of epithelial properties and the acquisition of migratory mesenchymal characteristics, termed the epithelial-mesenchymal transition (EMT). This transition is believed to be an essential step for carcinoma invasion and metastasis [2,3]. During EMT process, the loss of epithelial markers such as E-cadherin can occur through genetic or epigenetic mechanisms including aberrant DNA hypermethylation within the E-cadherin promoter [4] This finding suggests that a program of molecular alterations leading to EMT, invasion and metastasis can be modulated epigenetically

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Conclusion