title: Histone demethylase KDM5B collaborates with TFAP2C and Myc to repress the cell cycle inhibitor p21(cip) (CDKN1A).
abstract: The TFAP2C transcription factor has been shown to downregulate transcription of the universal cell cycle inhibitor p21(cip) (CDKN1A). In examining the mechanism of TFAP2C-mediated repression, we have identified a ternary complex at the proximal promoter containing TFAP2C, the oncoprotein Myc, and the trimethylated lysine 4 of histone H3 (H3K4me3) demethylase, KDM5B. We demonstrated that while TFAP2C and Myc can downregulate the CDKN1A promoter independently, KDM5B acts as a corepressor dependent on the other two proteins. All three factors collaborate for optimal CDKN1A repression, which requires the AP-2 binding site at -111/-103 and KDM5B demethylase activity. Silencing of TFAP2C-KDM5B-Myc led to increased H3K4me3 at the endogenous promoter and full induction of CDKN1A expression. Coimmunoprecipitation assays showed that TFAP2C and Myc associate with distinct domains of KDM5B and the TFAP2C C-terminal 270 amino acids (aa) are required for Myc and KDM5B interaction. Overexpression of all three proteins resulted in forced S-phase entry and attenuation of checkpoint activation, even in the presence of chemotherapy drugs. Since each protein has been linked to poor prognosis in breast cancer, our findings suggest that the TFAP2C-Myc-KDM5B complex promotes cell cycle progression via direct CDKN1A repression, thereby contributing to tumorigenesis and therapy failure.
authors.affiliation: Centre for Tumour Biology, Bart's Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Ping-Pui
authors.initials: PP
authors.lastname: Wong
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Miranda
authors.forename: KaYi V
authors.initials: KV
authors.lastname: Chan
authors.forename: Chiara
authors.initials: C
authors.lastname: Berlato
authors.forename: Helen C
authors.initials: HC
authors.lastname: Hurst
authors.forename: Angelo G
authors.initials: AG
authors.lastname: Scibetta
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D015536:Down-Regulation; D016259:Genes, myc; D056426:Genetic Loci; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D033962:Adaptor Protein Complex 2; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D012097:Repressor Proteins; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human