A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1.
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.
The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
W
W
Zhang
X
X
Zeng
K J
KJ
Briggs
R
R
Beaty
B
B
Simons
R-W
RW
Chiu Yen
M A
MA
Tyler
H-C
HC
Tsai
Y
Y
Ye
G S
GS
Gesell
J G
JG
Herman
S B
SB
Baylin
D N
DN
Watkins
D000818:Animals; D001943:Breast Neoplasms / Q000517:prevention & control*; D015536:Down-Regulation; D036382:Ephrin-A1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051379:Mice; D012097:Repressor Proteins / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D036382:Ephrin-A1; C499808:HIC1 protein, human; C096870:Hic1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins