title: NFX1 interacts with mSin3A/histone deacetylase to repress hTERT transcription in keratinocytes.
abstract: Transcription of the catalytic subunit of telomerase (hTERT) in keratinocytes can be induced by human papillomavirus type 16 (HPV16) E6/E6AP ubiquitin ligase through degradation of the repressor, NFX1-91. Here, we demonstrate that NFX1-91 interacts with the corepressor complex mSin3A/histone deacetylase (HDAC) at the hTERT promoter. By degrading NFX1-91, E6/E6AP changes the chromatin structure at the hTERT promoter as indicated by enhanced acetylation of histones H3 and H4 as well as dimethylation of H3K4. Knockdown of NFX1-91 by short hairpin RNA (shRNA) mimics the effect of E6 and leads to acetylation of histones H3 and H4. Conversely, knockdown of E6AP by shRNA suppresses histone acetylation at the hTERT promoter. These data demonstrate that targeted degradation of NFX1-91 by E6/E6AP dissociates the mSin3A/HDAC complex from the hTERT promoter and induces hTERT transcription.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Weifeng
authors.initials: W
authors.lastname: Luo
authors.forename: David J
authors.initials: DJ
authors.lastname: Elzi
authors.forename: Carla
authors.initials: C
authors.lastname: Grandori
authors.forename: Denise A
authors.initials: DA
authors.lastname: Galloway
mesh_terms: D000107:Acetylation; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004789:Enzyme Activation; D006207:Half-Life; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000201:enzymology* / Q000378:metabolism*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D019098:Telomerase / Q000235:genetics*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D002843:Chromatin; C068651:E6 protein, Human papillomavirus type 16; D006657:Histones; D050505:Mutant Proteins; C492666:NFX1 protein, human; D009856:Oncogene Proteins, Viral; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; C509186:TERT protein, human; D019098:Telomerase; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex