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.
Zhang
W
W
The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Zeng
X
X
Briggs
K J
KJ
Beaty
R
R
Simons
B
B
Chiu Yen
R-W
RW
Tyler
M A
MA
Tsai
H-C
HC
Ye
Y
Y
Gesell
G S
GS
Herman
J G
JG
Baylin
S B
SB
Watkins
D N
DN
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