Epithelial cell adhesion molecule (EpCAM) complex proteins promote transcription factor-mediated pluripotency reprogramming

Hsiang Po Huang, Pin Hsun Chen, Chun Ying Yu, Ching Yu Chuang, Lee Stone, Wen Chu Hsiao, Chung Leung Li, Shih Chih Tsai, Kai Yun Chen, Hsin Fu Chen, Hong Nerng Ho, Hung Chih Kuo

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that is highly expressed in embryonic stem cells (ESCs) and its role in maintenance of pluripotency has been suggested previously. In epithelial cancer cells, activation of the EpCAM surface-to-nucleus signaling transduction pathway involves a number of membrane proteins. However, their role in somatic cell reprogramming is still unknown. Here we demonstrate that EpCAM and its associated protein, Cldn7, play a critical role in reprogramming. Quantitative RT-PCR analysis of Oct4, Sox2, Klf4, and c-Myc (OSKM) infected mouse embryonic fibroblasts (MEFs) indicated that EpCAM and Cldn7 were upregulated during reprogramming. Analysis of numbers of alkaline phosphatase- and Nanog-positive clones, and the expression level of pluripotency-related genes demonstrated that inhibition of either EpCAM or Cldn7 expression resulted in impairment in reprogramming efficiency, whereas overexpression of EpCAM, EpCAM plus Cldn7, or EpCAM intercellular domain (EpICD) significantly enhanced reprogramming efficiency in MEFs. Furthermore, overexpression of EpCAM or EpICD significantly repressed the expression of p53 and p21 in the reprogramming MEFs, and both EpCAM and EpICD activated the promoter activity of Oct4. These observations suggest that EpCAM signaling may enhance reprogramming through up-regulation of Oct4 and possible suppression of the p53-p21 pathway. In vitro and in vivo characterization indicated that the EpCAM-reprogrammed iPSCs exhibited similar molecular and functional features to the mouse ESCs. In summary, our studies provide additional insight into the molecular mechanisms of reprogramming and suggest a more effective means of induced pluripotent stem cell generation.

Original languageEnglish
Pages (from-to)33520-33532
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number38
DOIs
Publication statusPublished - Sep 23 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Huang, H. P., Chen, P. H., Yu, C. Y., Chuang, C. Y., Stone, L., Hsiao, W. C., Li, C. L., Tsai, S. C., Chen, K. Y., Chen, H. F., Ho, H. N., & Kuo, H. C. (2011). Epithelial cell adhesion molecule (EpCAM) complex proteins promote transcription factor-mediated pluripotency reprogramming. Journal of Biological Chemistry, 286(38), 33520-33532. https://doi.org/10.1074/jbc.M111.256164