title: Genetic and epigenetic control of RKIP transcription.
abstract: Raf kinase inhibitory protein (RKIP) is known to modulate key signaling cascades and regulate normal physiological processes such as cellular proliferation, differentiation, and apoptosis. The expression of RKIP is found to be downregulated in several cancer metastases and the repressed RKIP expression can be reactivated on treatment with chemotherapeutic agents. RKIP is a proven tumor metastasis suppressor gene and investigating the mechanisms of transcriptional regulation of RKIP is therefore of immense clinical importance. In this review, we discuss the basal expression of RKIP in various tissues and the genetic aspects of the RKIP chromosomal locus including the structure of the RKIP promoter as well as gene regulatory elements such as enhancers. We also review the genetic and epigenetic modulation of RKIP transcription through EZH2, a component of the polycomb repressive complex 2 (PRC2) and sequence specific transcription factors (TFs) BACH1 and Snail. Emerging experimental evidence supports a unifying model in which both these TFs repress RKIP transcription in cancers by recruiting the EZH2 containing repressive complex to the proximal RKIP promoter. Finally, we review the known mechanisms employed by different types of chemotherapeutic agents to activate RKIP expression in cancer cells.
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio.
authors.forename: Ila
authors.initials: I
authors.lastname: Datar
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio.
authors.forename: Hanna
authors.initials: H
authors.lastname: Tegegne
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio.
authors.forename: Kevin
authors.initials: K
authors.lastname: Qin
authors.affiliation: Faculty of Medicine, Department of Pathology, Kuwait University Health Sciences Centre, Safat, Kuwait.
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.affiliation: Kuwait University, Faculty of Medicine, Safat, Kuwait.
authors.forename: Milad S
authors.initials: MS
authors.lastname: Bitar
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Trumbly
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio.
authors.forename: Kam C
authors.initials: KC
authors.lastname: Yeung
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein