Abstract 4533: Disruption of intrachromosomal interactions by deficient cohesin initiate epithelial-mesenchymal transition and stemness in cancer

Abstract

Abstract PURPOSE Although EMT-MET process is a crucial reversible event in development of human tumorigenesis controlled by complex networks, very little is known about how EMT-MET occurs reversibly and timely in cancer. Recently, different levels of Rad21 protein, a subunit of cohesin high-order-chromatin-architectural complex, between mesenchymal and epithelial cancers have been described. METHODS To elucidate how Rad21 determines EMT states, we silenced Rad21 in epithelial cancers using lentiviral shRNAs. We performed microarray to compare transcriptional changes by Rad21-KD. Additionally, we measured cell cycles and mitotic chromosome segregations to rule out the role of Rad21 as a sister chromatid segregation molecule. We observed cell morphology through confocal microscopy and checked high-order-chromatin structures using Chromosome-Conformation-Capture (3C) and Chromatin immunoprecipitation (ChIP) assay. RESULTS We identified high-order-chromatin structures mediated by Rad21 plays critical regulatory roles in transcription of EMT related genes for the first time. Rad21-KD in epithelial cancers caused reduction of Rad21 enrichment on TGFB1 and ITGA5 genes, leading to disruption of the-gene-specific-chromatin-looping structures. This dramatically recruited PolII and AcH3, active transcription marks, causing rapid induction of the gene transcriptions. Indeed, induced EMT-related genes directly led to morphological changes with EMT traits. We ultimately found that cancer stem cell-like cells showed same results with mesenchymal cancer and Rad21-KD epithelial cells. These findings indicate that the initiation of EMT in cancer might crucially require changes in high-order-chromatin structures of EMT-related genes mediated by cohesin, contributing to rapid and precise reversible changes in EMT or MET state to adapt to phenotypes of human cancer development. Citation Format: Jiyeon Yun. Disruption of intrachromosomal interactions by deficient cohesin initiate epithelial-mesenchymal transition and stemness in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4533.