title: Identification of p21 (CIP1/WAF1) as a direct target gene of HIC1 (Hypermethylated In Cancer 1).
abstract: The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor involved in the regulation of growth control and DNA damage response. We previously demonstrated that p57Kip2; a member of the CIP/KIP family of CDK (cyclin dependent kinase) inhibitors (CKI); is a direct target gene of HIC1 in quiescent cells. Here we show that ectopic expression of HIC1 in MDA-MB-231 cells or its overexpression in BJ-Tert fibroblasts induces decreased mRNA and protein expression of p21 (CIP1/WAF1) another member of this CKI family that plays essential roles in the p53-mediated DNA damage response. Conversely, knock-down of endogenous HIC1 in BJ-Tert through RNA interference up-regulates p21 in basal conditions and further potentiates this CKI in response to apoptotic etoposide-induced DNA damage. Through promoter luciferase activity and chromatin immunoprecipitation (ChIP), we demonstrate that HIC1 is a direct transcriptional repressor of p21. Thus, our results further demonstrate that HIC1 is a key player in the regulation of the DNA damage response.
authors.affiliation: 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.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dehennaut
authors.forename: Ingrid
authors.initials: I
authors.lastname: Loison
authors.forename: Gaylor
authors.initials: G
authors.lastname: Boulay
authors.forename: Capucine
authors.initials: C
authors.lastname: Van Rechem
authors.forename: Dominique
authors.initials: D
authors.lastname: Leprince
mesh_terms: D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D008156:Luciferases