title: Polycomb YY1 is a critical interface between epigenetic code and miRNA machinery after exposure to hypoxia in malignancy.
abstract: Yin Yang 1 (YY1) is a member of polycomb protein family involved in epigenetic modifications and transcriptional controls. We have shown that YY1 acts as positive regulator of tumor growth and angiogenesis by interfering with the VEGFA network. Yet, the link between polycomb chromatin complex and hypoxia regulation of VEGFA is still poorly understood. Here, we establish that hypoxia impairs YY1 binding to VEGFA mRNA 3'UTR (p<0.001) in bone malignancy. Moreover, RNA immunoprecipitation reveals the formation of triplex nuclear complexes among YY1, VEGFA DNA, mRNA, and unreached about 200 fold primiRNA 200b and 200c via Dicer protein. In this complex, YY1 is necessary to maintain the steady-state level of VEGFA expression while its silencing increases VEGFA mRNA half-life at 4 h and impairs the maturation of miRNA 200b/c. Hypoxia promotes histone modification through ubiquitination both of YY1 and Dicer proteins. Hypoxia-mediated down-regulation of YY1 and Dicer changes post-transcriptional VEGFA regulation by resulting in the accumulation of primiRNA200b/c in comparison to mature miRNAs (p<0.001). Given the regulatory functions of VEGFA on cellular activities to promote neoangiogenesis, we conclude that YY1 acts as novel critical interface between epigenetic code and miRNAs machinery under chronic hypoxia in malignancy.
authors: IRCCS, SDN, Via E. Gianturco 113, 80143 Naples, Italy.
authors: Teresa
authors: T
authors: Infante
authors: Department of Sciences and Technologies, University of Sannio, Benevento, Italy.
authors: Francesco P
authors: FP
authors: Mancini
authors: Department Multidisciplinary of Specialistic Medical Surgery and Odontostomatologic of Second University of Naples, Naples Italy.
authors: Alessandro
authors: A
authors: Lanza
authors: IRCCS, SDN, Via E. Gianturco 113, 80143 Naples, Italy.
authors: Andrea
authors: A
authors: Soricelli
authors: Department of Biochemistry Biophysics and General Pathology, Second University of Naples, Naples Italy. Electronic address: Filomena.denigris@unina2.it.
authors: Filomena
authors: F
authors: de Nigris
authors: IRCCS, SDN, Via E. Gianturco 113, 80143 Naples, Italy; Department of Biochemistry Biophysics and General Pathology, Second University of Naples, Naples Italy.
authors: Claudio
authors: C
authors: Napoli
mesh_terms: D001483:Base Sequence; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D035683:MicroRNAs; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D050986:YY1 Transcription Factor
keywords: Angiogenesis; Epigenetic; Hypoxia; VEGFa; YY1; miRNA