The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1 (Hypermethylated In Cancer 1)

•Overexpression of HIC1 in breast cancer cells reduces ApoER2 and VLDLR expression.•Knock-down of HIC1 in normal human fibroblasts increases ApoER2 and VLDLR expression.•HIC1 binds to the ApoER2 and VLDLR promoters to repress their transcription.•HIC1 regulates the Reelin-Dab1 pathway through the re...

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Published in:	Biochemical and biophysical research communications Vol. 440; no. 3; pp. 424 - 430
Main Authors:	Dubuissez, Marion, Faiderbe, Perrine, Pinte, Sébastien, Dehennaut, Vanessa, Rood, Brian R., Leprince, Dominique
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 25-10-2013 Elsevier
Subjects:	ApoER2 Base Sequence Cell Line, Tumor Cell Movement - genetics Cerebellum - cytology Cerebellum - growth & development DNA Methylation Gene Expression Regulation HIC1 Humans Kruppel-Like Transcription Factors - metabolism LDL-Receptor Related Proteins - genetics Life Sciences Lissencephaly Miller–Dieker syndrome Purkinje cells Purkinje Cells - metabolism Purkinje Cells - physiology Receptors, Cell Surface - genetics Receptors, LDL - genetics Tumor suppressor VLDLR Lissencephaly Purkinje cells VLDLR Miller–Dieker syndrome ApoER2 Tumor suppressor HIC1
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Summary:	•Overexpression of HIC1 in breast cancer cells reduces ApoER2 and VLDLR expression.•Knock-down of HIC1 in normal human fibroblasts increases ApoER2 and VLDLR expression.•HIC1 binds to the ApoER2 and VLDLR promoters to repress their transcription.•HIC1 regulates the Reelin-Dab1 pathway through the receptors ApoER2 and VLDLR.•These results implicate HIC1 in the regulation of neural cell migration. The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) is located in 17p13.3 a region frequently hypermethylated or deleted in tumors and in a contiguous-gene syndrome, the Miller-Dieker syndrome which includes classical lissencephaly (smooth brain) and severe developmental defects. HIC1 encodes a transcriptional repressor involved in the regulation of growth control, DNA damage response and cell migration properties. We previously demonstrated that the membrane-associated G-protein-coupled receptors CXCR7, ADRB2 and the tyrosine kinase receptor EphA2 are direct target genes of HIC1. Here we show that ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. Conversely, knock-down of endogenous HIC1 in BJ-Tert normal human fibroblasts through RNA interference results in the up-regulation of these two Reelin receptors. Finally, through chromatin immunoprecipitation (ChIP) in BJ-Tert fibroblasts, we demonstrate that HIC1 is a direct transcriptional repressor of ApoER2 and VLDLR. These data provide evidence that HIC1 is a new regulator of the Reelin pathway which is essential for the proper migration of neuronal precursors during the normal development of the cerebral cortex, of Purkinje cells in the cerebellum and of mammary epithelial cells. Deregulation of this pathway through HIC1 inactivation or deletion may contribute to its role in tumor promotion. Moreover, HIC1, through the direct transcriptional repression of ATOH1 and the Reelin receptors ApoER2 and VLDLR, could play an essential role in normal cerebellar development.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-291X 1090-2104
DOI:	10.1016/j.bbrc.2013.09.091