Transcription factor decoy: a pre-transcriptional approach for gene downregulation purpose in cancer

Abstract

Gene therapy as a therapeutic approach has been the dream for many scientists around the globe. Many strategies have been proposed and applied for this purpose, yet the void for a functional safe method is still apparent. Since most of the diseases are caused by undesirable upregulation (oncogenes) or downregulation (tumor suppressor genes) of genes, major gene therapy's techniques affect gene expression. Most of the methods are used in post-transcriptional level such as RNA inhibitory (RNAi) and splice-switching oligonucleotides (SSOs). RNAi blocks messenger RNA (mRNA) translation by mRNA degradation or interruption between attachments of mRNA with ribosomes' subunits. However, one of the novel methods is the usage of transcription factor targeted decoys. DNA decoys are the new generation of functional gene downregulatory oligonucleotides which compete with specific binding sites of transcription factors. Considering the exponential growth of this technique in both in vitro and in vivo studies, in this paper, we aim to line out the description, design, and application of decoys in research and therapy.

NF-κB as a Therapeutic Target in Inflammatory-Associated Bone Diseases

“…These approaches are highly specific and directly silence protein translation via siRNA or miRNA, or inhibit gene transactivation via decoy ODN. In particular, modulating the transcriptional process such as NF-κB by using the decoy ODN is an emerging approach due to the complexity of the signal transduction pathway (Rad et al, 2015). Synthetic decoy ODN is a short fragment of DNA which has the consensus sequence of the binding site of the target transcription factor, thus decoy ODN has the ability to bind to free target transcription factor subsequently preventing these factors from binding to the specific promoter regions (Bielinska, Shivdasani, Zhang, & Nabel, 1990).…”

Gene Therapy in Cancer Treatment: Why Go Nano?

“…The TFD-ODNs are short double-stranded DNA molecules with the sequence of a transcription factor of a particular gene, or the consensus DNA recognition motif of the transcription factor, competing with specific binding sites of transcription factors [109]. TFDs designed envisaging cancer therapy include TFDs targeting NF-KB for inhibition of metastasis, signal transducer and activator of transcription 3, or STAT3, to induce apoptosis and cell cycle arrest in ovarian, glioblastoma, lung and neck cancers (reviewed in [110]). Major challenges for the application of TFD-ODNs in cancer therapy include the design of TFDs, and stability in circulatory system and endosome [110].…”

Small-molecule Nucleic-acid-based Gene-silencing Strategies

“…Unlike antisense oligonucleotide approaches that target mRNA, decoys are short, doublestranded DNA molecules that compete with specific binding sites of transcription factors to prevent their binding at target promoters, in order to inhibit gene expression at pretranscription level. Since decoys are DNA, they are more stable and easy to handle than RNA-based intervention strategies [80]. Some methods, including the locked nucleic acid (LNA) introduced at the 3'-end [81] and chimeric decoys containing discrete binding sites [82], can increase decoys nuclease resistance and specificity.…”

“…Some methods, including the locked nucleic acid (LNA) introduced at the 3'-end [81] and chimeric decoys containing discrete binding sites [82], can increase decoys nuclease resistance and specificity. So far, numerous of studies have indicated that decoys are suited for novel potential therapeutic for combating cancer [80] and infectious diseases [83]. NOTCH1 decoy, a human IgG Fc consisting Notch1 extracellular domain inhibits tumor angiogenesis and growth by blocking Jagged-dependent activation of Notch signaling.…”