title: 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.
authors.affiliation: Science & Technology Department, BGI-Shenzhen, Shenzhen, P. R. China.
authors.forename: Juyong
authors.initials: J
authors.lastname: Zhang
authors.forename: Yue-Lei
authors.initials: YL
authors.lastname: Chen
authors.forename: Guanyu
authors.initials: G
authors.lastname: Ji
authors.forename: Weiying
authors.initials: W
authors.lastname: Fang
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Gao
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ding
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
mesh_terms: D000107:Acetylation / Q000187:drug effects; D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D006657:Histones; D010671:Phenylurea Compounds; D053773:Transforming Growth Factor beta1; D009536:Niacinamide; D000077157:Sorafenib; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases