Alternative‐splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics

Urbanski, Laura M.; Leclair, Nathan K.; Anczuków, Olga

doi:10.1002/wrna.1476

Cited by 287 publications

(364 citation statements)

References 448 publications

(744 reference statements)

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“…No recurrent somatic mutations in these SFs were detected in TCGA human breast tumors (Table S1A). This is in stark contrast to the recurrent SRSF2 mutations, centered on residue P95, detected in 20-30% of patients with myelodysplastic syndromes and 50% of those with chronic myelomonocytic leukemia (Urbanski et al, 2018). Together, these findings suggest that SF mutations are not likely to play a major role in breast cancer, in contrast to their role in myeloid tumors (Imielinski et al, 2012).…”

Section: Comprehensive Molecular Portrait Of Sf Alterations In Humanmentioning

confidence: 74%

“…Alterations in RNA splicing can lead to malignancy by affecting the expression of oncogene and tumor-suppressor isoforms (Biamonti et al, 2014). Tumor-associated aberrant alternative-splicing profiles result either from mutations in splicing-regulatory elements of specific cancer genes or from changes in the splicing machinery (Urbanski et al, 2018). Recurrent somatic mutations in selected components of the splicing machinery frequently occur in myeloid tumors, suggesting that splicing-factor (SF) alterations are a hallmark of cancer (Yoshida and Ogawa, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Recurrent somatic mutations in selected components of the splicing machinery frequently occur in myeloid tumors, suggesting that splicing-factor (SF) alterations are a hallmark of cancer (Yoshida and Ogawa, 2014). In solid tumors, SFs exhibit frequent changes in copy number and/or expression-level, but are rarely mutated (Urbanski et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis

Das

Akerman

et al. 2019

Preprint

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Misregulation of alternative splicing is a hallmark of human tumors; yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer, and uncover differences and redundancies in their targets and biological functions. We first identify splicing factors frequently altered in human breast tumors, and then assay their oncogenic functions using breast organoid models.Importantly we demonstrate that not all splicing factors affect mammary tumorigenesis. Specifically, upregulation of either SRSF4, SRSF6 or TRA2β promotes cell transformation and invasion. By characterizing the targets of theses oncogenic factors, we identify a shared set of spliced genes associated with well-established cancer hallmarks. Finally, we demonstrate that the splicing factor TRA2β is regulated by the MYC oncogene, plays a role in metastasis maintenance in vivo, and its levels correlate with breast-cancer-patient survival.3

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Section: Comprehensive Molecular Portrait Of Sf Alterations In Humanmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis

Das

Akerman

et al. 2019

Preprint

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“…These discoveries demonstrate the feasibility of small molecule-mediated RNA-selective splice modulation, as well as the potential for leveraging this strategy in other splicing diseases such as cancer. 127 Another promising example of splicing-targeted small molecules is GQC-05, an ellipticine G4 ligand, which targets the two alternative 5′ splice sites of apoptosis regulator Bcl-X pre-mRNA. 128 GQC-05 binding to Bcl-X pre-mRNA causes the direct alteration of the splicing sites Q2 and Q5 signified by a 15-fold fluorescent intensity increase and a shift in emission peak upon interaction of GQC-05 and the pre-mRNA, consistent with direct binding.…”

Section: Rna Splice Sitesmentioning

confidence: 99%

Unveiling the druggable RNA targets and small molecule therapeutics

Sztuba-Solińska

Chávez-Calvillo

Cline

2019

Bioorganic & Medicinal Chemistry

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Keywords:RNA structure and function RNA interactions Epitranscriptomics Small molecules RNA-based therapeutics RNA in disease Drug target A B S T R A C T The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets. RNA as a drug targetThe vast diversity of RNAs expanding beyond coding transcripts to several classes of ncRNAs that vary in length, biogenesis, polarity, and putative functions, increases the repertoire of druggable targets. 19,20 Here, specific RNA properties contribute to its attractive, yet challenging makeup as a target molecule. RNA can form complex three-dimensional structures through canonical Watson-Crick base pairing and complex tertiary interactions that are mediated by non-canonical bonds. Such structures can be as intricate and stable as those formed by proteins and can recognize small-molecule ligands, other nucleic acids, and/or proteins with high affinity and specificity. [21][22][23][24] At the same time, the highly dynamic conformation and repetitive character of its surface presents difficulties for drug design. 25,26 In addition, many putative small molecule-binding pockets in RNA are much more polar and solvent exposed than binding sites on proteins, complicating ligand design efforts. Compounding these issues, most target RNAs are expressed at low levels, with the exception of ribosomal (rRNA) and transfer (tRNA) RNAs, which constitute 80-90% and 10-15% of total cellular RNA, respectively. 27 Other abundant RNAs, such as messenger (mRNA), small nuclear (snRNA), and small nucleolar (snoRNA) are present at levels that are about 1-2 orders of magnitude lower than rRNA and tRNA. Certain small RNAs, such as micro (miRNA) and piwi (piRNAs) can be present at very high levels; however, this appears to be cell type dependent. One should keep in mind that if the RNA has catalytic activity or if it acts as a scaffold to regulate https://doi.

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“…Deregulated RNA splicing is emerging as a new hallmark of cancer following the discovery of several splicing factor genes harboring somatic mutations in different tumor types (Urbanski et al, 2018). SF3B1, a core component of the U2 snRNP, is the most frequently mutated splicing factor in human cancers.…”

Section: Introductionmentioning

confidence: 99%

CRISPR editing of sftb-1/SF3B1 in C. elegans allows the identification of synthetic interactions with cancer-related mutations and the chemical inhibition of splicing

Serrat

Kukhtar

Cornes

et al. 2019

Preprint

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SF3B1 is the most frequently mutated splicing factor in cancer. Mutations in SF3B1 confer growth advantages to cancer cells but they may also confer vulnerabilities that can be therapeutically targeted. In contrast to other animal models, SF3B1 cancer mutations can be maintained in homozygosis in C. elegans, allowing synthetic lethal screens with a homogeneous population of animals. These mutations cause alternative splicing (AS) defects in C. elegans, as it occurs in SF3B1-mutated human cells. In an RNAi screen, we identified U2 snRNP components as causing synthetic lethality with sftb-1/SF3B1 mutations.We also detected synthetic interactions between sftb-1 mutants and cancerrelated mutations in uaf-2/U2AF1 or rsp-4/SRSF2, demonstrating that this model can identify mutations that are mutually exclusive in human tumors.Thus, we have established a multicellular model amenable for high-throughput screening to uncover synthetic lethal interactions that could selectively kill cancer cells harboring SF3B1 mutations. 4 genetic manipulation of C. elegans, we established a multicellular model to study SF3B1 cancer-related mutations. Since the spliceosome components, and particularly SF3B1, are being intensively studied as a target of antitumor drugs (Bonnal, Vigevani and Valcárcel, 2012;Effenberger, Urabe and Jurica, 2017;DeNicola and Tang, 2019), the multicellular model of SF3B1 mutations described in this study would provide a convenient pre-clinical platform for identifying new targets and small molecules for use in cancer therapies. 5 RESULTS sftb-1, the C. elegans ortholog of SF3B1, is an ubiquitously expressed gene essential for developmentThe C. elegans protein SFTB-1 is 66% identical to human SF3B1 in terms of amino acid composition. Homology is particularly high at the HEAT domain, reaching 89% identity, and the most frequently mutated amino acids in cancer are conserved. The SFTB-1 sequence also conserves some of the U2AF ligand motifs (ULMs) that bind U2AF homology motifs (UHMs) present in other splicing factors (Figure 1A and S1) (Loerch et al., 2018).As expected for a core splicing factor, the CRISPR-engineered endogenous fluorescent reporter mCherry::SFTB-1 showed ubiquitous expression in somatic and germ cells, being absent in mature sperm only (Figure 1b and 1c). We also used CRISPR to generate the sftb-1(cer6) mutation, a deletion allele that produces a premature stop codon (Figure S2a) and causes an arrest at early larval stages, confirming that sftb-1 is essential for development (Figures 1d and 1e). sftb-1(cer6) homozygous animals completed embryonic development but arrested as larvae that could undergo few germ cell divisions (Figure S2b), suggesting that maternal wild-type (WT) product can still be present in the early larva.

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Alternative‐splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics

Cited by 287 publications

References 448 publications

Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis

Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis

Unveiling the druggable RNA targets and small molecule therapeutics

CRISPR editing of sftb-1/SF3B1 in C. elegans allows the identification of synthetic interactions with cancer-related mutations and the chemical inhibition of splicing

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