Modulation of RNA splicing as a potential treatment for cancer

Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
Bioengineered bugs 05/2011; 2(3):125-8. DOI: 10.4161/bbug.2.3.15165
Source: PubMed


Close to 90% of human genes are transcribed into pre-mRNA that undergoes alternative splicing, producing multiple mRNAs and proteins from single genes. This process is largely responsible for human proteome diversity, and about half of genetic disease-causing mutations affect splicing. Splice-switching oligonucleotides (SSOs) comprise an emerging class of antisense therapeutics that modify gene expression by directing pre-mRNA splice site usage. Bauman et al. investigated an SSO that up-regulated the expression of an anti-cancer splice variant while simultaneously eliminating an over-expressed cancer-causing splice variant. This was accomplished by targeting pre-mRNA of the apoptotic regulator Bcl-x, which is alternatively spliced to express anti- and pro-apoptotic splice variants Bcl-xL and Bcl-xS, respectively. High expression of Bcl-xL is a hallmark of many cancers and is considered a general mechanism used by cancer cells to evade apoptosis. Redirection of Bcl-x pre-mRNA splicing from Bcl-xL to -xS by SSO induced apoptotic and chemosensitizing effects in various cancer cell lines. Importantly, the paper shows that delivery of Bcl-x SSO using a lipid nanoparticle redirected Bcl-x splicing and reduced tumor burden in melanoma lung metastases. This was the first demonstration of SSO efficacy in tumors in vivo. SSOs are not limited to be solely potential anti-cancer drugs. SSOs were first applied to repair aberrant splicing in thalassemia, a genetic disease, they have been used to create novel proteins (e.g., ∆7TNFR1), and they have recently progressed to clinical trials for patients with Duchenne muscular dystrophy.

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    • "The use of the upstream 5 alternative splice site of bcl-x exon 2 produces Bcl-xS, which directly inhibits the pro-apoptotic Bcl-xL and Bcl-2 proteins. Targeting the downstream (bcl-xL) splice site with a 2 -O-Me redirects the splicing machinery to the upstream (bcl-xS) splice site, converting it into a pro-apoptotic molecule to reduce tumor growth [14]. Considering that up to 50% of human disease-causing mutations affect splicing, the SSO approach is emerging as a promising alternative to gene therapy. "
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    ABSTRACT: Peptides are versatile and attractive biomolecules that can be applied to modulate genetic mechanisms like alternative splicing. In this process, a single transcript yields different mature RNAs leading to the production of protein isoforms with diverse or even antagonistic functions. During splicing events, errors can be caused either by mutations present in the genome or by defects or imbalances in regulatory protein factors. In any case, defects in alternative splicing have been related to several genetic diseases including muscular dystrophy, Alzheimer's disease and cancer from almost every origin. One of the most effective approaches to redirect alternative splicing events has been to attach cell-penetrating peptides to oligonucleotides that can modulate a single splicing event and restore correct gene expression. Here, we summarize how natural existing and bioengineered peptides have been applied over the last few years to regulate alternative splicing and genetic expression. Under different genetic and cellular backgrounds, peptides have been shown to function as potent vehicles for splice correction, and their therapeutic benefits have reached clinical trials and patenting stages, emphasizing the use of regulatory peptides as an exciting therapeutic tool for the treatment of different genetic diseases. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Peptides
    • "TOES are complex modified antisense RNA oligonucleotides formed by two functionally distinct regions: the 5′ half of the oligo is complementary to a sequence within an exon of interest and is followed by a non-complementary RNA tail, designed to mimic an ESE sequence (Figure 1(c)). In this manner the oligo recruits specific trans-acting regulatory factors (such as SR proteins) and provides a sort of enhancer in trans that promotes exon inclusion [180, 186]. TOES have been first tested for their ability to induce the inclusion of SMN2 exon 7 in spinal muscular atrophy (SMA) patient fibroblasts [187]. "
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    ABSTRACT: Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.
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    • "Nevertheless, considering that AS plays a major role in the regulation of the apoptotic response (see C. Sette's review in this issue) and that AS variants have been demonstrated to regulate chemoresistance [103], it is reasonable that splicing modulation has been proposed as an appealing therapeutic target [135, 136]. Strategies to modulate AS by antisense oligonucleotides are already in advanced clinical trial phases for some neuromuscular disorders, such as Duchenne muscular dystrophy or spinal muscular atrophy, and oligonucleotides are being developed to target specific mRNA variants to enhance the efficacy of conventional chemotherapy [137]. In addition, in recent years several bacterial compounds, and other small molecules have been identified that target spliceosomal components [138]. "
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    ABSTRACT: It is widely accepted that tumorigenesis is a multistep process characterized by the sequential accumulation of genetic alterations. However, the molecular basis of genomic instability in cancer is still partially understood. The observation that hereditary cancers are often characterized by mutations in DNA repair and checkpoint genes suggests that accumulation of DNA damage is a major contributor to the oncogenic transformation. It is therefore of great interest to identify all the cellular pathways that contribute to the response to DNA damage. Recently, RNA processing has emerged as a novel pathway that may contribute to the maintenance of genome stability. In this review, we illustrate several different mechanisms through which pre-mRNA splicing and genomic stability can influence each other. We specifically focus on the role of splicing factors in the DNA damage response and describe how, in turn, activation of the DDR can influence the activity of splicing factors.
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