Abstract:Alternative splicing, a fundamental step in gene expression, is deregulated in many diseases. Splicing factors (SFs), which regulate this process, are up- or down regulated or mutated in several diseases including cancer. To date, there are no inhibitors that directly inhibit the activity of SFs. We designed decoy oligonucleotides, composed of several repeats of a RNA motif, which is recognized by a single SF. Here we show that decoy oligonucleotides targeting splicing factors RBFOX1/2, SRSF1 and PTBP1, can sp… Show more
“…This strategy was successfully used to target the activity of the splicing factors RBFOX1/2, PTBP1, and SRSF1. Importantly, the intracranial injection of an SRSF1-targeted DRO in a GBM mouse model decreased the oncogenic properties of cancer cells by reverting the splicing of oncogenic splice variants of SRSF1-target genes (INSR, U2AF1, MKNK2, USP8; see Table 2) [128]. These observations suggest that RNA-based therapeutic strategies may be useful to counteract brain tumorigenesis.…”
Section: Therapeutic Approachesmentioning
confidence: 97%
“…In some cases, these approaches have been also applied to brain tumors, eliciting promising pre-clinical results. In particular, ASOs targeting both protein-coding and regulatory non-coding RNA [126,127], sense oligonucleotides acting as decoy for specific splicing factors [128], or small drugs that modulate the activity of the spliceosome [53] have been tested in brain tumor models.…”
Section: Therapeutic Approachesmentioning
confidence: 99%
“…DROs are modified RNA molecules composed of a tandem binding motif for a specific splicing factor. The binding of splicing factors to DROs titers them out and inhibits their splicing activity towards endogenous targets [128]. This strategy was successfully used to target the activity of the splicing factors RBFOX1/2, PTBP1, and SRSF1.…”
Brain tumors are a heterogeneous group of neoplasms ranging from almost benign to highly aggressive phenotypes. The malignancy of these tumors mostly relies on gene expression reprogramming, which is frequently accompanied by the aberrant regulation of RNA processing mechanisms. In brain tumors, defects in alternative splicing result either from the dysregulation of expression and activity of splicing factors, or from mutations in the genes encoding splicing machinery components. Aberrant splicing regulation can generate dysfunctional proteins that lead to modification of fundamental physiological cellular processes, thus contributing to the development or progression of brain tumors. Herein, we summarize the current knowledge on splicing abnormalities in brain tumors and how these alterations contribute to the disease by sustaining proliferative signaling, escaping growth suppressors, or establishing a tumor microenvironment that fosters angiogenesis and intercellular communications. Lastly, we review recent efforts aimed at developing novel splicing-targeted cancer therapies, which employ oligonucleotide-based approaches or chemical modulators of alternative splicing that elicit an impact on brain tumor biology.
“…This strategy was successfully used to target the activity of the splicing factors RBFOX1/2, PTBP1, and SRSF1. Importantly, the intracranial injection of an SRSF1-targeted DRO in a GBM mouse model decreased the oncogenic properties of cancer cells by reverting the splicing of oncogenic splice variants of SRSF1-target genes (INSR, U2AF1, MKNK2, USP8; see Table 2) [128]. These observations suggest that RNA-based therapeutic strategies may be useful to counteract brain tumorigenesis.…”
Section: Therapeutic Approachesmentioning
confidence: 97%
“…In some cases, these approaches have been also applied to brain tumors, eliciting promising pre-clinical results. In particular, ASOs targeting both protein-coding and regulatory non-coding RNA [126,127], sense oligonucleotides acting as decoy for specific splicing factors [128], or small drugs that modulate the activity of the spliceosome [53] have been tested in brain tumor models.…”
Section: Therapeutic Approachesmentioning
confidence: 99%
“…DROs are modified RNA molecules composed of a tandem binding motif for a specific splicing factor. The binding of splicing factors to DROs titers them out and inhibits their splicing activity towards endogenous targets [128]. This strategy was successfully used to target the activity of the splicing factors RBFOX1/2, PTBP1, and SRSF1.…”
Brain tumors are a heterogeneous group of neoplasms ranging from almost benign to highly aggressive phenotypes. The malignancy of these tumors mostly relies on gene expression reprogramming, which is frequently accompanied by the aberrant regulation of RNA processing mechanisms. In brain tumors, defects in alternative splicing result either from the dysregulation of expression and activity of splicing factors, or from mutations in the genes encoding splicing machinery components. Aberrant splicing regulation can generate dysfunctional proteins that lead to modification of fundamental physiological cellular processes, thus contributing to the development or progression of brain tumors. Herein, we summarize the current knowledge on splicing abnormalities in brain tumors and how these alterations contribute to the disease by sustaining proliferative signaling, escaping growth suppressors, or establishing a tumor microenvironment that fosters angiogenesis and intercellular communications. Lastly, we review recent efforts aimed at developing novel splicing-targeted cancer therapies, which employ oligonucleotide-based approaches or chemical modulators of alternative splicing that elicit an impact on brain tumor biology.
“…While this contribution focuses on TFs binding to genomic decoy sites, these results are applicable to other classes of proteins, for example RNA-binding proteins binding to sites on RNA. [112][113][114][115] Our results show that degradation of decoy-bound TFs critically impacts both the mean and noise levels of the free TF pool. More specifically, while the average number of free (available) TFs monotonically decrease with increasing decoy abundance, the noise levels can sharply increase at low/intermediate decoy numbers before attenuating to Poisson levels as N → ∞ (Fig 2).…”
The genome contains several high-affinity non-functional binding sites for transcription factors (TFs) creating a hidden and unexplored layer of gene regulation. We investigate the role of such "decoy sites" in controlling noise (random fluctuations) in the level of a TF that is synthesized in stochastic bursts. Prior studies have assumed that decoy-bound TFs are protected from degradation, and in this case decoys function to buffer noise. Relaxing this assumption to consider arbitrary degradation rates for both bound/unbound TF states, we find rich noise behaviors. For low-affinity decoys, noise in the level of unbound TF always monotonically decreases to the Poisson limit with increasing decoy numbers. In contrast, for high affinity decoys, noise levels first increase with increasing decoy numbers, before decreasing back to the Poisson limit. Interestingly, while protection of bound TFs from degradation slows the time-scale of fluctuations in the unbound TF levels, decay of bounds TFs leads to faster fluctuations and smaller noise propagation to downstream target proteins. In summary, our analysis reveals stochastic dynamics emerging from nonspecific binding of TFs, and highlight the dual role of decoys as attenuators or amplifiers of gene expression noise depending on their binding affinity and stability of the bound TF.
“…The sequence analysis showed that there were several motifs (UCUCU) in the LHFPL3-AS1 precursor and LHFPL3-AS1-long (Fig. 6A ), which could be bound by PTBP1 protein 20 , suggesting that the splicing of LHFPL3-AS1 regulated by PTBP1 contribute to the biogenesis of LHFPL3-AS1-long. Fig.…”
Long noncoding RNAs (lncRNAs) are recognized as a new area for cancer therapy. B-cell lymphoma-2 (Bcl-2)-mediated suppression of apoptosis is an important molecular hallmark of cancer. However, the influence of lncRNA on the regulation of oncogenic Bcl-2 in cancer stem cells has not been explored. In this study, our findings revealed that the lncRNA LHFPL3-AS1-long, generated from the polypyrimidine tract binding protein 1 (PTBP1)-mediated splicing of the LHFPL3-AS1 precursor, upregulated BCL2 protein to contribute to tumorigenesis of melanoma stem cells. The in vitro and in vivo results showed that LHFPL3-AS1-long directly interacted with miR-181a-5p to inhibit the mRNA degradation of Bcl-2 (the target of miR-181), thus suppressing apoptosis of melanoma stem cells. The splicing factor PTBP1 regulated the alternative splicing of LHFPL3-AS1 transcript by preferentially binding to the motifs located in exon3 of LHFPL3-AS1 precursor, leading to the biogenesis of LHFPL3-AS1-long in melanoma stem cells. In patients with melanoma, the expressions of PTBP1 and LHFPL3-AS1 were significantly upregulated compared with the healthy donors. Therefore, our study revealed a mechanistic crosstalk among an onco-splicing factor, lncRNA and tumorigenesis of melanoma stem cells, enabling PTBP1 and LHFPL3-AS1 to serve as the attractive therapeutic targets for melanoma.
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