title: HEXIM1 down-regulates hypoxia-inducible factor-1α protein stability.
abstract: We have previously reported on the inhibition of HIF-1α (hypoxia-inducible factor α)-regulated pathways by HEXIM1 [HMBA (hexamethylene-bis-acetamide)-inducible protein 1]. Disruption of HEXIM1 activity in a knock-in mouse model expressing a mutant HEXIM1 protein resulted in increased susceptibility to the development of mammary tumours, partly by up-regulation of VEGF (vascular endothelial growth factor) expression, HIF-1α expression and aberrant vascularization. We now report on the mechanistic basis for HEXIM1 regulation of HIF-1α. We observed direct interaction between HIF-1α and HEXIM1, and HEXIM1 up-regulated hydroxylation of HIF-1α, resulting in the induction of the interaction of HIF-1α with pVHL (von Hippel-Lindau protein) and ubiquitination of HIF-1α. The up-regulation of hydroxylation involves HEXIM1-mediated induction of PHD3 (prolyl hydroxylase 3) expression and interaction of PHD3 with HIF-1α. Acetylation of HIF-1α has been proposed to result in increased interaction of HIF-1α with pVHL and induced pVHL-mediated ubiquitination, which leads to the proteasomal degradation of HIF-1α. HEXIM1 also attenuated the interaction of HIF-1α with HDAC1 (histone deacetylase 1), resulting in acetylation of HIF-1α. The consequence of HEXIM1 down-regulation of HIF-1α protein expression is attenuated expression of HIF-1α target genes in addition to VEGF and inhibition of HIF-1α-regulated cell invasion.
authors.affiliation: *Department of Pharmacology, Division of General Medical Science and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
authors.forename: I-Ju
authors.initials: IJ
authors.lastname: Yeh
authors.forename: Ndiya
authors.initials: N
authors.lastname: Ogba
authors.forename: Heather
authors.initials: H
authors.lastname: Bensigner
authors.forename: Scott M
authors.initials: SM
authors.lastname: Welford
authors.forename: Monica M
authors.initials: MM
authors.lastname: Montano
mesh_terms: D000107:Acetylation; D001943:Breast Neoplasms; D002465:Cell Movement; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D016601:RNA-Binding Proteins / Q000502:physiology*; D014157:Transcription Factors
chemical_list: C476123:HEXIM1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1