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

Yuniel Fernandez-Marrero; Daniel Bachmann; Emanuel Lauber; Thomas Kaufmann

doi:10.1016/j.isci.2018.11.005

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

iScience. 2018 Nov 30:9:461-474. doi: 10.1016/j.isci.2018.11.005. Epub 2018 Nov 10.

Authors

Yuniel Fernandez-Marrero¹, Daniel Bachmann¹, Emanuel Lauber¹, Thomas Kaufmann²

Affiliations

¹ Institute of Pharmacology, Faculty of Medicine, University of Bern, Inselspital, INO-F, 3010 Bern, Switzerland.
² Institute of Pharmacology, Faculty of Medicine, University of Bern, Inselspital, INO-F, 3010 Bern, Switzerland. Electronic address: thomas.kaufmann@pki.unibe.ch.

Abstract

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.

Keywords: Cancer; Molecular Mechanism of Gene Regulation.