The cancer stem cell marker CD133 interacts with plakoglobin and controls desmoglein-2 protein levels.
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ABSTRACT:
SUBMITTER: Koyama-Nasu R
PROVIDER: S-EPMC3542344 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
The cancer stem cell marker CD133 interacts with plakoglobin and controls desmoglein-2 protein levels.
Koyama-Nasu Ryo R Takahashi Rina R Yanagida Satoshi S Nasu-Nishimura Yukiko Y Oyama Masaaki M Kozuka-Hata Hiroko H Haruta Ryo R Manabe Emi E Hoshino-Okubo Akemi A Omi Hiroko H Yanaihara Nozomu N Okamoto Aikou A Tanaka Tadao T Akiyama Tetsu T
PloS one 20130110 1
The pentaspan membrane glycoprotein CD133 (also known as prominin-1) has been widely used as a marker for both cancer and normal stem cells. However, the function of CD133 has not been elucidated. Here we describe a cancer stem cell line established from clear cell carcinoma of the ovary (CCC) and show that CD133 interacts with plakoglobin (also known as γ-catenin), a desmosomal linker protein. We further demonstrate that knockdown of CD133 by RNA interference (RNAi) results in the downregulatio ...[more]
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Project description:MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.
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Project description:Colon cancer stem cells (CSCs), which are highly capable of self-renewal and proliferation, are involved in colon tumorigenesis and response to therapy. CD133 is considered the most robust surface marker for colorectal cancer stem cells. Although the TP53 gene is frequently mutated in colon cancer, it remains not fully understood whether and how tumor protein p53 (p53) is associated with CD133 expression in colon cancer cells. In the present study, the expression of the CSC biomarker CD133 was investigated in terms of p53 status in colorectal carcinoma HCT116 cells. p53 wild-type HCT116 (HCT116 p53+/+) and depleted HCT116 (HCT116 p53-/-) cells were used throughout this study. Cells carrying the CSC biomarkers CD133 and CD44 were examined by flow cytometry. A dual-luciferase reporter assay was employed to further confirm the transcriptional regulation of the CD133 promoter by p53. The results demonstrated that there was a significant difference in the % of CD133-positive cells between the HCT116 p53+/+ cell line (84.84±0.05%) and the HCT116 p53-/- cell line (4.13±0.02%). The mRNA expression levels of CD133 in HCT116 p53+/+ cells were also significantly higher compared with HCT116 p53-/- cells. Knockdown of p53 by specific small interfering RNA greatly reduced the expression of CD133 in HCT116 p53+/+ cells. Transcription factor binding site analysis indicated that there are several p53 binding elements in the CD133 promoter region. A dual-luciferase reporter assay further demonstrated the transcriptional activation of CD133 promoter by p53. In conclusion, these results suggest that p53 positively regulates the expression of CSC marker CD133 in the HCT116 human colon colorectal cancer cell line. p53 may be involved in the initiation and maintenance of colorectal cancer stem cells through regulating the expression of CD133.
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