Abstract
The transcriptional repressor HIC1 (Hypermethylated in Cancer 1) is a tumor suppressor gene inactivated in many human cancers including breast carcinomas. In this study, we show that HIC1 is a direct transcriptional repressor of β-2 adrenergic receptor (ADRB2). Through promoter luciferase activity, chromatin immunoprecipitation (ChIP) and sequential ChIP experiments, we demonstrate that ADRB2 is a direct target gene of HIC1, endogenously in WI-38 cells and following HIC1 re-expression in breast cancer cells. Agonist-mediated stimulation of ADRB2 increases the migration and invasion of highly malignant MDA-MB-231 breast cancer cells but these effects are abolished following HIC1 re-expression or specific down-regulation of ADRB2 by siRNA treatment. Our results suggest that early inactivation of HIC1 in breast carcinomas could predispose to stress-induced metastasis through up-regulation of the β-2 adrenergic receptor.
Highlights
The transcriptional repressor HIC1 is a tumor suppressor gene epigenetically silenced in many human tumors
We demonstrate that ADRB2 is a new direct target gene of HIC1
ADRB2 Is a Direct Target Gene of HIC1—We recently described the role of HIC1 in cell migration and invasion as partially relying on direct transcriptional repression of the tyrosine kinase receptor EphA2 gene
Summary
The transcriptional repressor HIC1 is a tumor suppressor gene epigenetically silenced in many human tumors. Conclusion: Early inactivation of HIC1 in breast carcinomas could predispose to stress-induced metastasis through up-regulation of the -2 adrenergic receptor. The transcriptional repressor HIC1 (Hypermethylated in Cancer 1) is a tumor suppressor gene inactivated in many human cancers including breast carcinomas. Chromatin immunoprecipitation (ChIP) and sequential ChIP experiments, we demonstrate that ADRB2 is a direct target gene of HIC1, endogenously in WI-38 cells and following HIC1 re-expression in breast cancer cells. Our results suggest that early inactivation of HIC1 in breast carcinomas could predispose to stress-induced metastasis through up-regulation of the -2 adrenergic receptor. Our recent results 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]. Our results suggest that HIC1 silencing, which occurs in the early stages of breast tumorigenesis, could contribute to later stages of tumor progression such as metastasis
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