title: The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1).
abstract: The tumor suppressor gene hypermethylated in cancer 1 (HIC1), which encodes a transcriptional repressor, is epigenetically silenced in many human tumors. Here, we show that ectopic expression of HIC1 in the highly malignant MDA-MB-231 breast cancer cell line severely impairs cell proliferation, migration, and invasion in vitro. In parallel, infection of breast cancer cell lines with a retrovirus expressing HIC1 also induces decreased mRNA and protein expression of the tyrosine kinase receptor EphA2. Moreover, chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. Taken together, our results identify EphA2 as a new direct target gene of HIC1. Finally, we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. To conclude, our results involve the tumor suppressor HIC1 in the transcriptional regulation of the tyrosine kinase receptor EphA2, whose ligand ephrin-A1 is also a HIC1 target gene. Thus, loss of the regulation of this Eph pathway through HIC1 epigenetic silencing could be an important mechanism in the pathogenesis of epithelial cancers.
authors.affiliation: CNRS UMR 8161, CNRS-Institut Pasteur de Lille-Université de Lille 1, 59021 Lille Cedex, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Foveau
authors.forename: Gaylor
authors.initials: G
authors.lastname: Boulay
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pinte
authors.forename: Capucine
authors.initials: C
authors.lastname: Van Rechem
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rood
authors.forename: Dominique
authors.initials: D
authors.lastname: Leprince
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D036104:Receptor, EphA2 / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators
chemical_list: C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; C089320:MTA1 protein, human; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; D036104:Receptor, EphA2; D006655:Histone Deacetylases