title: Dynamic cohesin-mediated chromatin architecture controls epithelial-mesenchymal plasticity in cancer.
abstract: Epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET) are important interconnected events in tumorigenesis controlled by complex genetic networks. However, the cues that activate EMT-initiating factors and the mechanisms that reversibly connect EMT/MET are not well understood. Here, we show that cohesin-mediated chromatin organization coordinates EMT/MET by regulating mesenchymal genes. We report that RAD21, a subunit of the cohesin complex, is expressed in epithelial breast cancer cells, whereas its expression is decreased in mesenchymal cancer. Depletion of RAD21 in epithelial cancer cells causes transcriptional activation of TGFB1 and ITGA5, inducing EMT. Reduced binding of RAD21 changes intrachromosomal chromatin interactions within the TGFB1 and ITGA5 loci, creating an active transcriptional environment. Similarly, stem cell-like cancer cells also show an open chromatin structure at both genes, which correlates with high expression levels and mesenchymal fate characteristics. Conversely, overexpression of RAD21 in mesenchymal cancer cells induces MET-specific expression patterns. These findings indicate that dynamic cohesin-mediated chromatin structures are responsible for the initiation and regulation of essential EMT-related cell fate changes in cancer.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Yun
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Song
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hwang-Phill
authors.initials: HP
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Yi
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology Seoul National University College of Medicine, Seoul, Korea Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea kimty@snu.ac.kr.
authors.forename: Tae-You
authors.identifier: 0000-0002-9986-2684
authors.initials: TY
authors.lastname: Kim
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D053773:Transforming Growth Factor beta1; D000097722:Cohesins; C429022:RAD21 protein, human; C508960:TGFB1 protein, human
keywords: EMT; cancer stem cell; cohesin; higher‐order chromatin structure