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Critical Reviews™ in Oncogenesis
SJR: 0.946 SNIP: 0.503 CiteScore™: 2

ISSN Print: 0893-9675
ISSN Online: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2014012025
pages 417-430

Genetic and Epigenetic Control of RKIP Transcription

Ila Datar
Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio
Hanna Tegegne
Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio
Kevin Qin
Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio
Fahd Al-Mulla
Faculty of Medicine, Department of Pathology, Kuwait University Health Sciences Centre, Safat, Kuwait
Milad S. Bitar
Kuwait University, Faculty of Medicine, Safat, Kuwait
Robert J. Trumbly
Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio
Kam C. Yeung
Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, Ohio

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.