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c-Rel is a transcriptional repressor of EPHB2 in colorectal cancer

Tao Fu1, Peng Li, Hanzhi Wang

  • 1Department of General Surgery, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.

The Journal of Pathology
|July 22, 2009
PubMed

Insights

Colorectal cancers often lose EPHB2 expression. Researchers found that c-Rel represses EPHB2 transcription, explaining this loss and offering new therapeutic targets for colorectal cancer.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • EPHB2, a receptor tyrosine kinase, regulates intestinal epithelial architecture.
  • Loss of EPHB2 expression is common in colorectal cancer despite Wnt pathway activation.
  • Mechanisms driving EPHB2 down-regulation in colorectal cancer remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms responsible for EPHB2 down-regulation in colorectal cancer.
  • To identify transcriptional factors involved in controlling EPHB2 expression in colon cancer cells.

Main Methods:

  • Analysis of EPHB2 gene 5'-flanking region for regulatory elements.
  • Electrophoretic gel mobility shift assays (EMSA) to assess protein-DNA binding.
  • Chromatin immunoprecipitation (ChIP) assays to confirm in vivo binding.
  • RNA interference (RNAi) to knockdown c-Rel expression.
  • Transient transfection assays to evaluate c-Rel's effect on EPHB2 expression.

Main Results:

  • DNA hypermethylation does not cause EPHB2 loss in colorectal cancer.
  • A negative regulatory element in the EPHB2 5'-flanking region was identified.
  • c-Rel was found to directly bind to this regulatory element.
  • Inhibition or knockdown of c-Rel increased EPHB2 expression in colon cancer cells.
  • Over-expression of c-Rel repressed endogenous EPHB2 expression.

Conclusions:

  • c-Rel acts as a transcriptional repressor of the EPHB2 gene.
  • c-Rel plays an active role in the down-regulation of EPHB2 in colorectal cancers.
  • These findings elucidate a novel mechanism of EPHB2 regulation in cancer and suggest c-Rel as a potential therapeutic target.

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