Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy

Salton, Maayan; Misteli, Tom

doi:10.1016/j.molmed.2015.11.005

Cited by 135 publications

(134 citation statements)

References 85 publications

(115 reference statements)

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“…Alternative splicing, as an important process that modifies mRNA isoforms, allows cells to generate a great number of protein and mRNA isoforms with diverse functional and regulatory properties. The plasticity of alternative splicing is often exploited by cancer cells to produce isoform switches that promote cancer cell survival, proliferation, metastasis and drug resistance (35). Differential isoform expression in human tumors correlates with the cancer progression (36,37).…”

Section: Discussionmentioning

confidence: 99%

Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment

et al. 2018

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Numerous genes are arranged in complex overlapping and interlaced patterns, and such arrangements potentially contribute to the regulation of gene expression. Previous studies have demonstrated that a region in chromosome 19q13.2-3 encompassing the overlapping genes excision repair cross-complementation group 1 (ERCC1), CD3e molecule associated protein (CD3EAP) and protein phosphatase 1 regulatory subunit 13 like (PPP1R13L) was found to be associated with the risk and prognosis of non-small cell lung cancer (NSCLC). The present study confirmed the hypothesis that there are co-expression patterns among these overlapping genes. The suggestive bioinformatic evidence of The Cancer Genome Atlas was verified by quantitative polymerase chain reaction (qPCR) analysis of NSCLC tissue samples. In addition, a cisplatin-induced DNA damage cell model was assessed by microarray analysis, qPCR and 3' rapid amplification of cDNA ends (3'RACE) to verify and quantify the expression levels of co-expressed alternative splicing isoforms in the NSCLC tissues, as well as in cancer A549 and normal 16HBE cells. The expression of CD3EAP exon 1 was demonstrated to be significantly associated with PPP1R13L exon 1, while CD3EAP exon 3 was significantly associated with ERCC1 exon 11 in normal and NSCLC tissues. It was observed that short transcripts of ERCC1, CD3EAP and PPP1R13L are co-expressed in A549 cells and full-length transcripts are co-expressed in 16HBE cells. Furthermore, a novel transcriptional regulation pattern was described based on the positional associations of overlapping genes. The region encompassing the overlapping genes ERCC1, CD3EAP and PPP1R13L may be involved in linking the upstream and downstream genes, while the different splicing isoforms of ERCC1 affect the expression of its overlapping genes, suggesting potential application in cisplatin resistance in NSCLC treatment.

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Section: Discussionmentioning

confidence: 99%

Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment

et al. 2018

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“…Despite many exposés, whether new confessions of ULM extensions, phosphorylation-sensitivity, and cooperative binding will emerge as recurring dramas among UHM-ULM partners for now remain tantalizing family secrets. In the longer term, understanding the interplay among UHMs and ULMs may offer new therapeutic avenues for targeting the spliceosome (for review, see Bonnal et al 2012), which has been highlighted recently for MYCdriven malignancies (Hirsch et al 2015;Hsu et al 2015;Koh et al 2015) and already is promising for compounds that target the ULM-containing protein SF3b155 (for review, see Salton and Misteli 2016).…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

Loerch

Kielkopf

2016

RNA

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U2AF homology motifs (UHM) that recognize U2AF ligand motifs (ULM) are an emerging family of protein-protein interaction modules. UHM-ULM interactions recur in pre-mRNA splicing factors including U2AF1 and SF3b1, which are frequently mutated in myelodysplastic syndromes. The core topology of the UHM resembles an RNA recognition motif and is often mistakenly classified within this large family. Here, we unmask the charade and review recent discoveries of UHM-ULM modules for protein-protein interactions. Diverse polypeptide extensions and selective phosphorylation of UHM and ULM family members offer new molecular mechanisms for the assembly of specific partners in the early-stage spliceosome.

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“…In addition, mutations in splicing‐related genes have also been found in various solid cancers, including lung, breast, and pancreatic cancers (Dvinge et al , ). In parallel with clinical observations, the attractiveness of the pharmacological modulation of pre‐mRNA splicing as a cancer therapy strategy has also increased (Bonnal et al , ; Lee & Abdel‐Wahab, ; Salton & Misteli, ).…”

Section: Introductionmentioning

confidence: 99%

Anti‐tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC‐dependent vulnerability

et al. 2018

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The modulation of pre‐mRNA splicing is proposed as an attractive anti‐neoplastic strategy, especially for the cancers that exhibit aberrant pre‐mRNA splicing. Here, we discovered that T‐025 functions as an orally available and potent inhibitor of Cdc2‐like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T‐025 reduced CLK‐dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo. Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive‐associated biomarker of T‐025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T‐025 treatment. MYC activation, which altered pre‐mRNA splicing without the transcriptional regulation of CLKs, rendered cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti‐tumor efficacy of T‐025 in an allograft model of spontaneous, MYC‐driven breast cancer, at well‐tolerated dosage. Collectively, our results suggest that the novel CLK inhibitor could have therapeutic benefits, especially for MYC‐driven cancer patients.

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Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy

Cited by 135 publications

References 85 publications

Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment

Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

Anti‐tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC‐dependent vulnerability

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