Transcriptional repression of cancer stem cell marker CD133 by tumor suppressor p53

다국어 초록 (Multilingual Abstract)

Novel therapeutic strategies are needed to overcome cancer recurrence, metastasis, and resistance to chemo- and radiotherapy. Cancer stem cells (CSC) are major contributors to the malignant transformation of cells due to their capacity for self-renewal. Although various CSC markers have been identified in several types of tumors, they are primarily used as cancer prediction markers and for the isolation of CSC populations. CD133, one of the best-characterized CSC markers in distinct solid tumor types, was shown to be correlated with CSC tumor-initiating capacity; however, the regulation of CD133 expression and its function in cancer are poorly understood. Here, we show that CD133 expression is negatively regulated by direct binding of the p53 tumor suppressor protein to a non-canonical p53-binding sequence in the CD133 promoter. Binding of p53 recruits Histone Deacetylase 1 (HDAC1) to the CD133 promoter and subsequently suppresses CD133 expression by reducing histone H3 acetylation. Furthermore, CD133 depletion suppresses tumor cell proliferation, colony formation, and the expression of core stemness transcription factors including NANOG, octamer-bindingtranscriptionfactor4 (OCT4), SOX2 and c-MYC. Critically, the anti-proliferative effects of p53 are antagonized by rescue of CD133 expression in a p53 over-expressing cell line, indicating that the tumor suppressive activity of p53 might be mediated by CD133 suppression. Taken together, our results suggest that p53-mediated transcriptional regulation of CD133 is a key underlying mechanism for controlling the growth and tumor-initiating capacity of CSCs and provide a novel perspective on targeting CSCs for cancer therapy.

목차 (Table of Contents)

• Ⅰ. Introduction
• 1. Cancer Stem Cell 01
• 1.1. Cancer Stem Cell theory 01
• 1.2. Cancer Stem Cell marker 06
• 2. CD133 08
• 2.1. cancer stem cell marker CD133 08
• 2.2. Function of CD133 in cellular signal 11
• 3. Tumor suppressor p53 14
• 4. Cancer stem cell and p53 17
• 5. Aims of this study 19
• Ⅱ. Result
• 1. Effect of various drug on the CD133 in CD133 high-expressing cells 20
• 2. Inverse correlation of tumor suppressor p53 and CD133 expression 22
• 3. CD133 down-regulation by stress-induced activation of p53 26
• 4. Suppressing CD133 expression by direct regulation of p53 29
• 5. Requirement of p53 for suppressing CD133 expression in p53 null H1299 cell line 32
• 6. Transcriptional regulation of CD133 by p53 34
• 7. Physical Interaction of p53 and HDAC1 40
• 8. CD133 is required for tumor growth and survival 42
• 9. CD133 inhibition is required for p53 tumor-suppressive activity 47
• Ⅲ. Discussion 50
• Ⅳ. Material and methods 54
• Ⅴ. References 61
• Ⅵ. 국문요약 73