title: ΔNp63α represses anti-proliferative genes via H2A.Z deposition.
abstract: ΔNp63α is a member of the p53 family of transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because ΔNp63α and p53 bind virtually identical DNA sequence motifs, it has been proposed that ΔNp63α functions as a dominant-negative inhibitor of p53 to promote proliferation and block apoptosis. However, most SCCs concurrently overexpress ΔNp63α and inactivate p53, suggesting the autonomous action of these oncogenic events. Here we report the discovery of a novel mechanism of transcriptional repression by ΔNp63α that reconciles these observations. We found that although both proteins bind the same genomic sites, they regulate largely nonoverlapping gene sets. Upon activation, p53 binds all enhancers regardless of ΔNp63α status but fails to transactivate genes repressed by ΔNp63α. We found that ΔNp63α associates with the SRCAP chromatin regulatory complex involved in H2A/H2A.Z exchange and mediates H2A.Z deposition at its target loci. Interestingly, knockdown of SRCAP subunits or H2A.Z leads to specific induction of ΔNp63α-repressed genes. We identified SAMD9L as a key anti-proliferative gene repressed by ΔNp63α and H2A.Z whose depletion suffices to reverse the arrest phenotype caused by ΔNp63α knockdown. Collectively, these results illuminate a molecular pathway contributing to the autonomous oncogenic effects of ΔNp63α.
authors.affiliation: Howard Hughes Medical Institute.
authors.forename: Corrie L
authors.initials: CL
authors.lastname: Gallant-Behm
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ramsey
authors.forename: Claire L
authors.initials: CL
authors.lastname: Bensard
authors.forename: Ignacio
authors.initials: I
authors.lastname: Nojek
authors.forename: Jack
authors.initials: J
authors.lastname: Tran
authors.forename: Minghua
authors.initials: M
authors.lastname: Liu
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Espinosa
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D049109:Cell Proliferation; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C077020:histone H2A.F-Z