title: Cooperation of p300 and PCAF in the control of microRNA 200c/141 transcription and epithelial characteristics.
abstract: Epithelial to mesenchymal transition (EMT) not only occurs during embryonic development and in response to injury, but is an important element in cancer progression. EMT and its reverse process, mesenchymal to epithelial transition (MET) is controlled by a network of transcriptional regulators and can be influenced by posttranscriptional and posttranslational modifications. EMT/MET involves many effectors that can activate and repress these transitions, often yielding a spectrum of cell phenotypes. Recent studies have shown that the miR-200 family and the transcriptional suppressor ZEB1 are important contributors to EMT. Our previous data showed that forced expression of SPRR2a was a powerful inducer of EMT and supports the findings by others that SPRR gene members are highly upregulated during epithelial remodeling in a variety of organs. Here, using SPRR2a cells, we characterize the role of acetyltransferases on the microRNA-200c/141 promoter and their effect on the epithelial/mesenchymal status of the cells. We show that the deacetylase inhibitor TSA as well as P300 and PCAF can cause a shift towards epithelial characteristics in HUCCT-1-SPRR2a cells. We demonstrate that both P300 and PCAF act as cofactors for ZEB1, forming a P300/PCAF/ZEB1 complex on the miR200c/141 promoter. This binding results in lysine acetylation of ZEB1 and a release of ZEB1 suppression on miR-200c/141 transcription. Furthermore, disruption of P300 and PCAF interactions dramatically down regulates miR-200c/141 promoter activity, indicating a PCAF/P300 cooperative function in regulating the transcriptional suppressor/activator role of ZEB1. These data demonstrate a novel mechanism of miRNA regulation in mediating cell phenotype.
authors.affiliation: Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Mizuguchi
authors.forename: Susan
authors.initials: S
authors.lastname: Specht
authors.forename: John G
authors.initials: JG
authors.lastname: Lunz
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.forename: Natasha
authors.initials: N
authors.lastname: Corbitt
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takizawa
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055233:Cornified Envelope Proline-Rich Proteins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D004848:Epithelium / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D008957:Models, Genetic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D014158:Transcription, Genetic; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D055233:Cornified Envelope Proline-Rich Proteins; D035683:MicroRNAs; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; C543718:Mirn141 microRNA, mouse; C543719:Mirn200 microRNA, mouse; C101744:SPRR2A protein, human; C491091:Sprr2a1 protein, mouse