Targeting Splicing in Prostate Cancer

Antonopoulou, Effrosyni; Ladomery, Michael

doi:10.3390/ijms19051287

Cited by 19 publications

(17 citation statements)

References 155 publications

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“…Small molecule inhibitors have been successfully employed to target splicing factors, splicing factor kinases, or upstream splicing regulators and to alter mRNA splicing patterns. Likewise, siRNAs and SSOs have also been applied to specifically target and disrupt the splicing regulatory sequences or splicing factor/RNA interactions at the pre-mRNA level [ 188 , 189 ]. SF3B1-targeting agents, such as spliceostatins, pladienolides and herboxidienes, are small molecule inhibitors used to disrupt the early stage of spliceosome assembly [ 188 ].…”

Section: Therapeutic Strategies For Correcting Aberrant Splicing Ementioning

confidence: 99%

“…H3B-8800, another splicing modulator targeting SF3B1, inhibits expression of aberrant splice variant MAP3K7 in a dose-dependent manner and preferentially kills epithelial and hematologic malignancies expressing mutant spliceosome components [ 191 ]. Besides splicing factors ( Figure 4 A), the targeting of splicing factor kinases, such as the CDC2-like kinases (CLKs) and serine-arginine protein kinases (SRPKs), has emerged as a potential therapy to reverse aberrant RNA splicing [ 188 , 189 ]. For example, small molecule inhibitor SRPIN340 blocks SRPK1-mediated phosphorylation of SRSF1 [ 192 ], leading to splice switching of pro-angiogenic VEGFA165 to anti-angiogenic VEGFA165b in prostate cancer and leukemic cells [ 193 , 194 ].…”

Section: Therapeutic Strategies For Correcting Aberrant Splicing Ementioning

confidence: 99%

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Aberrant RNA Splicing in Cancer and Drug Resistance

Wang

Lee

2018

Cancers

140

109

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More than 95% of the 20,000 to 25,000 transcribed human genes undergo alternative RNA splicing, which increases the diversity of the proteome. Isoforms derived from the same gene can have distinct and, in some cases, opposing functions. Accumulating evidence suggests that aberrant RNA splicing is a common and driving event in cancer development and progression. Moreover, aberrant splicing events conferring drug/therapy resistance in cancer is far more common than previously envisioned. In this review, aberrant splicing events in cancer-associated genes, namely BCL2L1, FAS, HRAS, CD44, Cyclin D1, CASP2, TMPRSS2-ERG, FGFR2, VEGF, AR and KLF6, will be discussed. Also highlighted are the functional consequences of aberrant splice variants (BCR-Abl35INS, BIM-γ, IK6, p61 BRAF V600E, CD19-∆2, AR-V7 and PIK3CD-S) in promoting resistance to cancer targeted therapy or immunotherapy. To overcome drug resistance, we discuss opportunities for developing novel strategies to specifically target the aberrant splice variants or splicing machinery that generates the splice variants. Therapeutic approaches include the development of splice variant-specific siRNAs, splice switching antisense oligonucleotides, and small molecule inhibitors targeting splicing factors, splicing factor kinases or the aberrant oncogenic protein isoforms.

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Section: Therapeutic Strategies For Correcting Aberrant Splicing Ementioning

confidence: 99%

Section: Therapeutic Strategies For Correcting Aberrant Splicing Ementioning

confidence: 99%

Aberrant RNA Splicing in Cancer and Drug Resistance

Wang

Lee

2018

Cancers

140

109

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“…Characterization of the AS landscape in cancers via reliable big data to identify biomarkers provides a wealth of insight into cancers with excellent prognostic value. Hence, increasing evidence has indicated that AS is actively involved in the initiation, progression and prognosis of cancers [4,5]. Additionally, cancer researchers realize the significant clinical utility of AS and its potential as a useful therapeutic signaling target [6–8].…”

Section: Introductionmentioning

confidence: 99%

Role of global aberrant alternative splicing events in papillary thyroid cancer prognosis

Lin

Huang

et al. 2019

Aging

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Background: Alternative splicing events have been increasingly reported for anomalous perturbations in various cancers, including papillary thyroid cancer (PTC). Methods: Integration analysis of RNA sequencing and clinical information were utilized to identify survival associated splicing events in PTC. Then, several prognosis-related splicing events were submitted to develop moderate predictors for survival monitoring by using least absolute shrinkage and selection operator model. In addition, several biomedical computational algorithms were conducted to identify pathways enriched by genes with prognostic splicing events and construct regulatory network dominated by splicing factors. Results: Survival analysis in 496 PTC patients indicated that TNM stage, tumor stage, distant metastasis and tumor status were significantly correlated with PTC patients' progression-free interval. 2799 splicing events were identified as prognostic molecular events. Functional enrichment analysis suggested that prognostic splicing events are associated with several energy metabolism-related processes. Based on these prognostic events, several prognostic signatures were developed. The final prognostic signature acted as an independent prognostic factor after adjusting for several clinical parameters. Interestingly, splicing regulatory network was constructed to display potential regulatory mechanisms of splicing events in PTC. Conclusions: Our analysis provides the status of splicing events involved in the progression and may represent an underappreciated hallmark of PTC.

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“…In prostate cancer, our area of interest, the most notable splicing change is the emergence of the ligand-independent androgen receptor ARV7 isoform in response to hormone deprivation (3). Other examples include proangiogenic splice variants of VEGFA (4), tumorigenic variants of the transcription factors ERG and KLF6 (5,6), and antiapoptotic splicing of BCL2L2 (7,8). However, the intersection of upstream oncogenic signaling, pre-mRNA splicing, and the biological processes affected by those splicing events has not been defined at a global level.…”

mentioning

confidence: 99%

Pathway-guided analysis identifies Myc-dependent alternative pre-mRNA splicing in aggressive prostate cancers

Phillips

Pan

Tsai

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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We sought to define the landscape of alternative pre-mRNA splicing in prostate cancers and the relationship of exon choice to known cancer driver alterations. To do so, we compiled a metadataset composed of 876 RNA-sequencing (RNA-Seq) samples from five publicly available sources representing a range of prostate phenotypes from normal tissue to drug-resistant metastases. We subjected these samples to exon-level analysis with rMATS-turbo, purposebuilt software designed for large-scale analyses of splicing, and identified 13,149 high-confidence cassette exon events with variable incorporation across samples. We then developed a computational framework, pathway enrichment-guided activity study of alternative splicing (PEGASAS), to correlate transcriptional signatures of 50 different cancer driver pathways with these alternative splicing events. We discovered that Myc signaling was correlated with incorporation of a set of 1,039 cassette exons enriched in genes encoding RNA binding proteins. Using a human prostate epithelial transformation assay, we confirmed the Myc regulation of 147 of these exons, many of which introduced frameshifts or encoded premature stop codons. Our results connect changes in alternative pre-mRNA splicing to oncogenic alterations common in prostate and many other cancers. We also establish a role for Myc in regulating RNA splicing by controlling the incorporation of nonsense-mediated decay-determinant exons in genes encoding RNA binding proteins.alternative splicing | prostate cancer | Myc | rMATS | PEGASAS A lternative pre-mRNA splicing is a regulated process that governs exon choice and greatly diversifies the proteome. It is an essential process that contributes to development, tissue specification, and homeostasis and is often dysregulated in disease states (1). In cancer, this includes growth signaling, epithelial-tomesenchymal transition, resistance to apoptosis, and treatment resistance (2). In prostate cancer, our area of interest, the most notable splicing change is the emergence of the ligand-independent androgen receptor ARV7 isoform in response to hormone deprivation (3). Other examples include proangiogenic splice variants of VEGFA (4), tumorigenic variants of the transcription factors ERG and KLF6 (5, 6), and antiapoptotic splicing of BCL2L2 (7, 8). However, the intersection of upstream oncogenic signaling, pre-mRNA splicing, and the biological processes affected by those splicing events has not been defined at a global level.Prostate cancers progress from hormone-responsive, localized disease to hormone-independent, metastatic disease accompanied by changes in gene expression and mutations that confer cellautonomous growth and therapeutic resistance (9). The study of disease progression from primary prostate adenocarcinoma (PrAd) to metastatic, castration-resistant prostate cancer (mCRPC) and treatment-related neuroendocrine prostate cancer (NEPC) has been aided by large-scale genomic and transcriptomic studies of patient samples representing each form of the disease (10-13). E...

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Targeting Splicing in Prostate Cancer

Cited by 19 publications

References 155 publications

Aberrant RNA Splicing in Cancer and Drug Resistance

Aberrant RNA Splicing in Cancer and Drug Resistance

Role of global aberrant alternative splicing events in papillary thyroid cancer prognosis

Pathway-guided analysis identifies Myc-dependent alternative pre-mRNA splicing in aggressive prostate cancers

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