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Acetylation and activation of STAT3 mediated by nuclear translocation of CD44

Jia-Lin Lee1, Mei-Jung Wang, Jeou-Yuan Chen

  • 1Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Republic of China.

The Journal of Cell Biology
|June 10, 2009
PubMed

Insights

Cancer stem cell marker CD44 translocates to the nucleus, reprogramming cell fate by binding promoters like cyclin D1. This novel mechanism involves CD44 complexing with STAT3 and p300 to enhance cyclin D1 expression and cell proliferation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • CD44, a type I transmembrane glycoprotein, is a recognized marker for cancer stem cells.
  • CD44's role in cancer progression and its intracellular functions are areas of ongoing investigation.

Purpose of the Study:

  • To elucidate the novel function of CD44 in transcriptional regulation.
  • To investigate the mechanism of CD44 internalization, nuclear translocation, and its impact on gene expression.

Main Methods:

  • Utilized techniques to track CD44 internalization and nuclear localization.
  • Mapped the bipartite nuclear localization signal (NLS) in the CD44 cytoplasmic tail.
  • Investigated the interaction of CD44 with STAT3 and p300 using biochemical assays.
  • Analyzed the effect of CD44 on cyclin D1 promoter activity and gene expression.

Main Results:

  • Engaged CD44 is internalized and translocated to the nucleus.
  • Nuclear CD44 binds to promoters, including cyclin D1, mediating transcriptional reprogramming.
  • Internalized CD44 forms a complex with STAT3 and p300, inducing STAT3 acetylation and dimerization independently of external signals.
  • A bipartite NLS in CD44's cytoplasmic tail directs its nuclear translocation; a CD44(NLS) mutant retains STAT3 in the cytosol.
  • Acetylated STAT3 dimers, associated with CD44, bind the cyclin D1 promoter, increasing its expression and promoting cell proliferation.

Conclusions:

  • CD44 possesses a novel function in transcriptional modulation via nuclear translocation.
  • The CD44-STAT3-p300 complex regulates cyclin D1 expression, driving cell proliferation.
  • This pathway represents a new mechanism by which cancer stem cell markers influence tumor progression.

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