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

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.

Loss of Hypermethylated in Cancer 1 (HIC1) in Breast Cancer Cells Contributes to Stress-induced Migration and Invasion through β-2 Adrenergic Receptor (ADRB2) Misregulation

“…Recent studies and our results demonstrate that HIC1 re-expression strongly impairs these phenotypes in breast cancer cells (15,34). ADRB2 repression consistently sup- ports these observations although re-expression of a transcription factor involves a network of multiple target genes, which in the case of HIC1, seem to be involved in cell cycle regulation (8,15) and cell motility (14,34).…”

“…Our recent results also demonstrate a role for HIC1 in the regulation of cell migration and invasion. These biological effects are partially mediated through transcriptional repression of the ligand/receptor couple EFNA1 and EphA2 in different cells (15,34).…”

“…To date, ten target genes play supporting roles in developmental and cell cycle control: histone deacetylase SIRT1 (10), the transcription factors ATOH1 (11), Sox9 (12), and ⌬Np73 (13), the G-protein coupled receptor CXCR7 (14), Cyclin D1 and P57KIP2 (CDKN1C) (8) and EFNA1, a cell surface ligand for Eph tyrosine kinase receptors (15).…”

HIC1 Silencing in Triple-Negative Breast Cancer Drives Progression through Misregulation of LCN2

“…Recently, downstream target genes of HIC1 responsible for developmental and cell-cycle control have been identified, including the histone deacetylase SIRT1 (11), the transcription factor ATOH1 (12), the G-protein-coupled receptor CXCR7 (13,14), Cyclin D1, P57KIP2 (CDKN1C; ref. 9), and ephrin-A1, a cell surface ligand for Eph tyrosine kinase receptors (15). However, given the many potential physiologic roles of HIC1, few HIC1 target genes have been characterized.…”

Differential Regulation of HIC1 Target Genes by CtBP and NuRD, via an Acetylation/SUMOylation Switch, in Quiescent versus Proliferating Cells

“…To date, SIRT1, ATOH1 (a proneuronal transcription factor) (4), E2F1, CXCR7 (a receptor for the chemokine CXCL12) (62), and ephrin-A1 (a cell surface ligand for Eph receptors) (72) are the only characterized direct target genes of HIC1.…”