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

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.

Clinicopathological examination of dipeptidase�1 expression in colorectal cancer

“…However, as the EMT process may be a 'druggable' target by specific inhibitors, candidate therapeutic targets are being developed. Sorafenib is one example of a drug that inhibits EMT via histone modifications that occur during EMT in lung adenocarcinoma cell lines (24). Currently, sorafenib is used for cases with an activating mutation of A-Raf proto-oncogene, serine/threonine kinase (25); with further research, sorafenib may be administered to CRC patients.…”

EMT: Present and future in clinical oncology

“…). Sorafenib reverses histone modifications related to EMT in lung carcinoma cells (Zhang et al ., ), and mocetinostat is a histone deacetylase (HDAC) inhibitor able to reverse the EMT phenotype and sensitize resistant PCa cells to docetaxel by restoring miR ‐ 203 expression and promoting ZEB1 inhibition (Meidhof et al ., ).…”

Regulation of Gene Expression by Sodium Valproate in Epithelial-to-Mesenchymal Transition

“…Therefore, comprehensive gene expression analysis has recently been conducted using microarray analysis [8,9]. Moreover, epigenetic changes such as DNA methylation [6,10] and histone modification [11,12] affect the regulation of gene expression through localization around gene loci, and were shown to be important in EMT. Because histone acetylation is down-regulated in whole cells during fibrosis, histone deacetylase (HDAC) inhibitors have been used to suppress this reduction.…”