The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1 (Hypermethylated In Cancer 1).
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.
CNRS-UMR 8161, Institut de Biologie de Lille, Université de Lille Nord de France, Institut Pasteur de Lille, IFR 142, 1 rue Calmette, BP447, 59017 Lille Cedex, France.
Marion
M
Dubuissez
Perrine
P
Faiderbe
Sébastien
S
Pinte
Vanessa
V
Dehennaut
Brian R
BR
Rood
Dominique
D
Leprince
D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D000091042:Reelin Protein
C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D026502:LDL-Receptor Related Proteins; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C469363:reelin receptor; C000717127:RELN protein, human
ApoER2; HIC1; Lissencephaly; Miller–Dieker syndrome; Purkinje cells; Tumor suppressor; VLDLR