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

Abstract

SummaryBCL-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.

Melanoma Stem Cell-Like Phenotype and Significant Suppression of Immune Response within a Tumor Are Regulated by TRIM28 Protein

“…TRIM28 gene is highly expressed in different cancer types, and higher expression frequently correlates with poor patient prognosis [ 14 , 15 , 37 , 38 , 39 ]. Recently, Fernandez-Marrero Y. et al [ 40 ] have reported a significant association of TRIM28 expression with the survival of melanoma patients. Using three independent datasets (SKCM TCGA, GSE65904, and GSE19234), we also demonstrated that TRIM28 upregulation is associated with a dramatically lower survival rate of melanoma patients.…”

The BCL-2 selective inhibitor ABT-199 sensitizes soft tissue sarcomas to proteasome inhibition by a concerted mechanism requiring BAX and NOXA

“…Indeed, BOK and MCL-1 have been proposed to interact at least functionally and constitute a regulatory feedback 52 . Non-proteasomal regulation of BOK expression by mRNA stability, as proposed by Oyneagucha et al 52 , was also published by Fernandez-Marrero et al 53 . Thus, there is increasing evidence that there are levels of regulation for the expression of BOK other than proteasomal degradation.…”

The Multifaceted Roles of the BCL-2 Family Member BOK

“…Of note, TRIM28 and BOK levels were found to be negatively correlated in selected cancers such as hepatocellular carcinoma and kidney cancer. In those cancers, high BOK and low TRIM28 mRNA levels correlated with increased survival, and low BOK and high TRIM28 levels with decreased survival (Fernandez-Marrero et al, 2018). Translational silencing of BOK mRNA by miRNA miR-296-5p was reported by Onyeagucha et al (2017) in human breast cancer cell lines.…”

“…At the level of mRNA stability and translation, BOK was found to be downregulated by binding of the miRNA miR-296-5p to its 3' UTR in breast cancer cells (Onyeagucha et al, 2017). Furthermore, destabilizing (AU/U)-rich elements [one AU-rich element (ARE) site in mouse Bok, two U-rich element (URE) sites in human BOK] were recently described in the 3' UTR of BOK (Fernandez-Marrero et al, 2018). In that study, the authors identified tripartite motif containing 28 (TRIM28), a large pleiotropic protein that is known for its many roles at the genomic level in the nucleus (Czerwinska et al, 2017), as a novel URE-binding protein triggering the degradation of human BOK mRNA (Figure 3; Fernandez-Marrero et al, 2018).…”

“…BOK mRNA stability is negatively regulated by the presence of one ARE in the mouse and two URE in the human 3' UTR (Fernandez-Marrero et al, 2018). TRIM28 was identified as one of the factors binding to the UREs in human BOK mRNA, leading to its degradation.…”