Abstract
Upregulation of the proto-oncogene Twist1 is highly correlated with acquired drug resistance and poor prognosis in human cancers. Altered expression of this multifunctional transcription factor is also associated with inherited skeletal malformations. The mammalian Twist1 3′UTRs are highly conserved and contain a number of potential regulatory elements including miRNA target sites. We analyzed the translational regulation of TWIST1 using luciferase reporter assays in a variety of cell lines. Among several miRNAs tested, miR-145a-5p, miR-151-5p and a combination of miR-145a-5p + miR-151-5p and miR-151-5p + miR-337-3p were able to significantly repress Twist1 translation. This phenomena was confirmed with both exogenous and endogenous miRNAs and was dependent on the presence of the predicted target sites in the 3′UTR. Furthermore, the repression was sensitive to LNA-modified miRNA antagonists and resulted in decreased migratory potential of murine embryonic fibroblast cells. Understanding the in vivo mechanisms of this oncogene's regulation might open up a possibility for therapeutic interference by gene specific cancer therapies.
Highlights
The evolutionary conserved basic helix-loop-helix transcription factor TWIST1 is a multifunctional proto-oncogene with a strong correlation to poor prognosis
Analysis of Twist1 39UTR Translational regulation of mRNAs is typically mediated through evolutionary conserved regulatory regions within the UTRs. To test if this is the case for Twist1, we compared the conservation of coding sequence (CDS) and 39UTR of Twist1 mRNA among selected amniotes. 59UTRs were not included since the full-length sequences are not available for all species
The 39UTR of Twist1 contains considerably more potential regulatory sequences, namely four nuclear polyadenylation signals, two cytoplasmic polyadenylation elements (CPEs), one AU-rich sequence and a number of putative miRNA target sites predicted by several algorithms (TargetScan, miRBase and PicTar)
Summary
The evolutionary conserved basic helix-loop-helix (bHLH) transcription factor TWIST1 is a multifunctional proto-oncogene with a strong correlation to poor prognosis. TWIST1 is able to inhibit c-MYC induced apoptosis [1] and directly regulates the expression of several other oncogenes such as GLI1 [2], miR-10b [3] and AKT2 [4]. Twist expression is regulated by a complex network of signals and has been described as an integrator of SHH, FGF and BMP signaling [6]. A number of transcription factor binding sites have been identified in the Twist upstream region and direct binding of transcriptional activators like NF-kB [8] and repressors like Prospero-related homeobox 1 (PROX1) [9] has been shown
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