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The Role of Histone demethylase, UTX in Breast Cancer Stem cell and Epithelial-Mesenchymal Transition

Title
The Role of Histone demethylase, UTX in Breast Cancer Stem cell and Epithelial-Mesenchymal Transition
Author
최희주
Alternative Author(s)
Choi, Heejoo
Advisor(s)
공구
Issue Date
2014-02
Publisher
한양대학교
Degree
Master
Abstract
UTX, a member of Jumonji C family of protein, is a histone demethylase that specifically demethylates di- and trimethylated lysine 27 of histone H3 (H3K27) to antagonize a histone methyltransferase EZH2. The H3K27 trimethylation by EZH2 has been known to be associated with the mechanisms leading tumorigenesis, invasion, metastasis and cancer stem cell (CSC) in many tumors including breast cancer. However, the role of UTX in cancer progression has not been identified yet. In this study, I demonstrated that loss of UTX enhances self-renewal of breast CSC and epithelial to mesenchymal transition (EMT) through regulating EMT transcription factors. I observed that shRNA-mediated UTX knockdown leads to expansion of breast CSC population and improved self-renewal properties which were assayed both by measuring tumorsphere formation and anchorage independent ability in immortalized and breast cancer cell lines. Furthermore, UTX knockdown in MCF-10A cells induced mesenchymal-like morphological change, migration and invasion potentials, as well as down-regulation of epithelial markers, E-cadherin and β-catenin and up-regulation of mesenchymal markers, N-cadherin and vimentin. Consistently, UTX overexpression repressed EMT properties in MDA-MB-231 invasive breast cancer cells. I also found that UTX positively regulates E-cadherin, a key marker of EMT, by repressing EMT transcription factors, Snail, ZEB1 and ZEB2 during EMT. These effects were not reversed by EZH2 knockdown, indicating that the regulation of EMT and CSC by UTX is independent of EZH2 expression. Notably, UTX facilitated epigenetic silencing of EMT transcription factors by cooperating with c-Myc and several epigenetic modulators. Inactivation of UTX led to recruitment of c-Myc and to dissociation HDAC1and DNMT1 from promoter of EMT transcription factors and consequently increased the level of H3K4me2 and H3ac and decreased the DNA methylation at these promoters. Taken together, these observations provided that UTX negatively regulates CSC and CSC-related EMT, but it is independently H3K27 demethylation, suggesting a tumor suppressive role of UTX act as a novel epigenetic modifier of EMT transcription factors in breast cancer.
URI
https://repository.hanyang.ac.kr/handle/20.500.11754/131033http://hanyang.dcollection.net/common/orgView/200000423424
Appears in Collections:
GRADUATE SCHOOL OF BIOMEDICAL SCIENCE AND ENGINEERING[S](의생명공학전문대학원) > BIOMEDICAL SCIENCE(의생명과학과) > Theses (Master)
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