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Role of CBX7 in breast cancer stem cell regulation

Title
Role of CBX7 in breast cancer stem cell regulation
Other Titles
CBX7의 유방암줄기세포 조절 기전
Author
김혜연
Alternative Author(s)
김혜연
Advisor(s)
공구
Issue Date
2014-02
Publisher
한양대학교
Degree
Master
Abstract
Chromoprotein homologue 7 (CBX7) is a member of the polycomb repressive complex (PRC)-1 which play an important role in several biological processes including stem cell regulation, differentiation, and cancer developments via epigenetic regulation of gene expression together with PRC-2. However, the role of CBX7 in cancer stem cell (CSC) regulation and tumorigenicity of human breast cancers remains unknown. Here, this study demonstrated that CBX7 has a tumor suppressive function by negatively regulating breast CSCs. I found that CBX7 expression was downregulated in population of breast CSCs compared with non-CSCs. Furthermore, small-hairpin RNA (shRNA)-mediated CBX7 knockdown in MCF10A immortalized breast cell lines and MDA-MB-231 breast cancer cell lines showed the increased percentage of CD44+/CD24-/ESA+ breast CSC population and reinforced self-renewal of breast CSCs as confirmed by flow cytometry, tumorsphere forming and anchorage independent growth assays. Similarly, tetracycline-inducible CBX7 overexpression in MCF7 breast cancer cell lines reduced percentage and self-renewal activity of breast CSCs. Consistently, xenograft with CBX7 knockdown MDA-MB-231 cells exhibited the enhanced in vivo tumor-initiating ability. I also identified a PcG-independent regulatory mechanism of breast CSCs by CBX7. Using a gene expression microarray analysis, I found that several identified CBX7-target genes including diminished expression of Dickkopf-1 (DKK-1) were involved in the Wnt signaling pathway. Moreover, I confirmed that CBX7 positively regulates the expression of DKK-1, a Wnt antagonist, by cooperating with p300 acetyltransferase to enhance the histone acetylation of DKK-1 promoter. Consistent with this observation, CBX7 inhibited GSK3-β phosphorylation, nuclear translocation of β-catenin and subsequent TCF/LEF promoter activity and its target c-Myc expression, indicating the negative regulation of the Wnt/-catenin/TCF pathway by CBX7. Furthermore, treatment with DKK-1 inhibitor, WAY-262611, in CBX7 overexpressing breast cancer cells showed recovery of the Wnt signaling pathway and consequent rescue of breast CSC activity. Taken together, these findings suggested that CBX7 acts as a novel epigenetic modifier of DKK-1 gene by cooperating with p300 and inhibits breast CSC activity through DKK-1-mediated suppression of the Wnt signaling pathway. Therefore, CBX7 could be a crucial tumor suppressor as a novel negative regulator of breast CSCs.
URI
https://repository.hanyang.ac.kr/handle/20.500.11754/131032http://hanyang.dcollection.net/common/orgView/200000423392
Appears in Collections:
GRADUATE SCHOOL OF BIOMEDICAL SCIENCE AND ENGINEERING[S](의생명공학전문대학원) > BIOMEDICAL SCIENCE(의생명과학과) > Theses (Master)
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