Negative Regulation of BOK Expression by Recruitment of TRIM28 to Regulatory Elements in Its 3′ Untranslated Region

• Published in: iScience Vol. 9; pp. 461 - 474
• Main Authors: Fernandez-Marrero, Yuniel, Bachmann, Daniel, Lauber, Emanuel, Kaufmann, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier 30.11.2018
• Subjects: Molecular Mechanism of Gene Regulation; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2018.11.005

BCL-2-related ovarian killer (BOK) is a pro-apoptotic BAX-like member of the BCL-2 family with suggested tumor suppressor activity. The molecular mechanisms regulating BOK expression are poorly understood and fail to explain a frequent lack of concordance between protein and transcript levels. Here, we describe a potent post-transcriptional mechanism that negatively regulates BOK expression mediated by conserved (AU/U)-rich elements within its 3' UTR. Using proteomics approaches we identified TRIM28 as a key component associating with U-rich elements in the human BOK 3' UTR, resulting in a dramatic reduction of BOK expression. TRIM28 is overexpressed in several cancers, correlating with poor patient outcome, whereas the BOK locus is frequently deleted or its expression downregulated in human cancers. Data mining indicated that, for certain cancers, high TRIM28 and low BOK expression are significantly correlated in the stratum of patients with the worst survival, suggesting that this mechanism might be of potential therapeutic value.