A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1

W. Zhang, X. Zeng, K. J. Briggs, R. Beaty, B. Simons, Ray-Whay Yen, M. A. Tyler, H. C. Tsai, Y. Ye, G. S. Gesell, J. G. Herman, Stephen B Baylin, D. N. Watkins

Research output: Contribution to journalArticle

Abstract

The tumor suppressor gene hypermethylated in cancer 1 (HIC1), which encodes a transcriptional repressor, is epigenetically inactivated in various human cancers. In this study, we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers. We also show that mouse embryos lacking both Hic1 alleles manifest developmental defects spatially associated with the misexpression of ephrin-A1, and that overexpression of ephrin-A1 is a feature of tumors arising in Hic1 heterozygous mice in which the remaining wild-type allele is epigenetically silenced. In breast cancer, we find that ephrin-A1 expression is common in vivo, but that in cell culture, expression of the EphA receptors is predominant. Restoration of HIC1 function in breast cancer cells leads to a reduction in tumor growth in vivo, an effect that can be partially rescued by co-overexpression of ephrin-A1. Interestingly, overexpression of ephrin-A1 in vitro triggers downregulation of EphA2 and EphA4 levels, resulting in an expression pattern similar to that seen in vivo. We conclude that Hic1 spatially restricts ephrin-A1 expression in development, and that upregulated expression of ephrin-A1 resulting from epigenetic silencing of HIC1 in cancer cells may be an important mechanism in epithelial malignancy.

Original languageEnglish (US)
Pages (from-to)2467-2476
Number of pages10
JournalOncogene
Volume29
Issue number17
DOIs
StatePublished - Apr 2010

Fingerprint

Ephrin-A1
Breast Neoplasms
Neoplasms
Alleles
Eph Family Receptors
Tumor Suppressor Genes
Epigenomics

Keywords

  • EphA2
  • EphA4
  • Ephrin-A1
  • Hic1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Zhang, W., Zeng, X., Briggs, K. J., Beaty, R., Simons, B., Yen, R-W., ... Watkins, D. N. (2010). A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1. Oncogene, 29(17), 2467-2476. https://doi.org/10.1038/onc.2010.12

A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1. / Zhang, W.; Zeng, X.; Briggs, K. J.; Beaty, R.; Simons, B.; Yen, Ray-Whay; Tyler, M. A.; Tsai, H. C.; Ye, Y.; Gesell, G. S.; Herman, J. G.; Baylin, Stephen B; Watkins, D. N.

In: Oncogene, Vol. 29, No. 17, 04.2010, p. 2467-2476.

Research output: Contribution to journalArticle

Zhang, W, Zeng, X, Briggs, KJ, Beaty, R, Simons, B, Yen, R-W, Tyler, MA, Tsai, HC, Ye, Y, Gesell, GS, Herman, JG, Baylin, SB & Watkins, DN 2010, 'A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1', Oncogene, vol. 29, no. 17, pp. 2467-2476. https://doi.org/10.1038/onc.2010.12
Zhang, W. ; Zeng, X. ; Briggs, K. J. ; Beaty, R. ; Simons, B. ; Yen, Ray-Whay ; Tyler, M. A. ; Tsai, H. C. ; Ye, Y. ; Gesell, G. S. ; Herman, J. G. ; Baylin, Stephen B ; Watkins, D. N. / A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1. In: Oncogene. 2010 ; Vol. 29, No. 17. pp. 2467-2476.
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