Genetic and epigenetic control of RKIP transcription

Ila Datar, Hanna Tegegne, Kevin Qin, Fahd Al-Mulla, Milad Sami Bitar, Robert J. Trumbly, Kam C. Yeung

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)417-430
Number of pages14
JournalCritical Reviews in Oncogenesis
Volume19
Issue number6
DOIs
Publication statusPublished - 1 Jan 2014

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Keywords

  • Enhancer
  • Epigenetics
  • RKIP
  • Transcription initiation
  • Transcription regulation

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