title: Regulation of the high basal expression of the manganese superoxide dismutase gene in aggressive breast cancer cells.
abstract: A high basal expression of manganese superoxide dismutase (MnSOD) has been reported in aggressive breast cancer cells, according to an unknown mechanism, and contributes to their invasive abilities. Here, we report the involvement of Sp1 and nuclear factor-κB (NF-κB) transcription factors in this high basal expression of MnSOD in aggressive breast cancer cells. Suppression or inactivation of Sp1 showed that it plays an essential role in the high MnSOD expression in aggressive breast cancer cells through a unique binding site identified by chromatin immunoprecipitation (ChIP) assay and functional analysis of the MnSOD proximal promoter. Treatment of cells with a specific NF-κB inhibitor peptide decreased significantly high basal MnSOD expression. A ChIP assay showed binding of a constitutive p50/p65 NF-κB complex to the MnSOD intronic enhancer element, associated with hyperacetylation of the H3 histone. Finally, high basal expression of MnSOD resulted in the lack of expression of Damaged DNA binding 2 (DDB2) protein in aggressive breast cancer cells. DDB2 overexpression prevented the binding of Sp1 as well as of NF-κB to their respective elements on the MnSOD gene. These results contribute to a better understanding of MnSOD up-regulation, which may be clinically important in the prediction of breast tumor progression.
authors.affiliation: EA 4421 Signalisation, Génomique et Recherche Translationnelle en Oncologie, Faculté des Sciences, Université Henri Poincaré, Nancy-Université, 54506 Vandoeuvre-lès-Nancy Cedex, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Ennen
authors.forename: Vanessa
authors.initials: V
authors.lastname: Minig
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Grandemange
authors.forename: Nadège
authors.initials: N
authors.lastname: Touche
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Merlin
authors.forename: Vanessa
authors.initials: V
authors.lastname: Besancenot
authors.forename: Emilie
authors.initials: E
authors.lastname: Brunner
authors.forename: Lionel
authors.initials: L
authors.lastname: Domenjoud
authors.forename: Philippe
authors.initials: P
authors.lastname: Becuwe
mesh_terms: D000107:Acetylation; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005260:Female; D005609:Free Radicals; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D005609:Free Radicals; D006657:Histones; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D013482:Superoxide Dismutase