title: Distinct mechanisms for opposite functions of homeoproteins Cdx2 and HoxB7 in double-strand break DNA repair in colon cancer cells.
abstract: Homeobox genes, involved in embryonic development and tissues homeostasis in adults, are often deregulated in cancer, but their relevance in pathology is far from being fully elucidated. In colon cancers, we report that the homeoproteins HoxB7 and Cdx2 exhibit different heterogeneous patterns, Cdx2 being localized in moderately altered neoplasic glands in contrast to HoxB7 which predominates in poorly-differentiated areas; they are coexpressed in few cancer cells. In human colon cancer cells, both homeoproteins interact with the DNA repair factor KU70/80, but functional studies reveal opposite effects: HoxB7 stimulates DNA repair and cell survival upon etoposide treatment, whereas Cdx2 inhibits both processes. The stimulatory effect of HoxB7 on DNA repair requires the transactivation domain linked to the homeodomain involved in the interaction with KU70/80, whereas the transactivation domain of Cdx2 is dispensable for its inhibitory function, which instead needs the homeodomain to interact with KU70/80 and the C-terminal domain. Thus, HoxB7 and Cdx2 respectively use transcription-dependent and -independent mechanisms to stimulate and inhibit DNA repair. In addition, in cells co-expressing both homeoproteins, Cdx2 lessens DNA repair activity through a novel mechanism of inhibition of the transcriptional function of HoxB7, whereby Cdx2 forms a molecular complex with HoxB7 and prevents it to recognize its target in the chromatin. These results point out the complex interplay between the DSB DNA repair activity and the homeoproteins HoxB7 and Cdx2 in colon cancer cells, making the balance between these factors a determinant and a potential indicator of the efficacy of genotoxic drugs.
authors.affiliation: INSERM UMR_S1113, 3 avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, Faculté de Médecine, FMTS, 67081 Strasbourg, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Soret
authors.affiliation: INSERM UMR_S1113, 3 avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, Faculté de Médecine, FMTS, 67081 Strasbourg, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Martin
authors.affiliation: INSERM UMR_S1113, 3 avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, Faculté de Médecine, FMTS, 67081 Strasbourg, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Duluc
authors.affiliation: Université de Strasbourg, Faculté de Médecine, FMTS, 67081 Strasbourg, France; CNRS UMR7242, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 67412 Illkirch, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Dantzer
authors.affiliation: INSERM UMR_S1113, 3 avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, Faculté de Médecine, FMTS, 67081 Strasbourg, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vanier
authors.affiliation: INSERM UMR_S1113, 3 avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, Faculté de Médecine, FMTS, 67081 Strasbourg, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gross
authors.affiliation: INSERM UMR_S1113, 3 avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, Faculté de Médecine, FMTS, 67081 Strasbourg, France.
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Freund
authors.affiliation: INSERM UMR_S1113, 3 avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, Faculté de Médecine, FMTS, 67081 Strasbourg, France. Electronic address: Claire.domon@inserm.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Domon-Dell
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045325:HCT116 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; C490538:HOXB7 protein, human; D018398:Homeodomain Proteins; C093253:Hoxb7 protein, mouse; D014157:Transcription Factors
keywords: Homeobox gene; KU complex; Nontranscriptional; Transcription