Function, clinical application, and strategies of Pre-mRNA splicing in cancer

Chen, Di; Syafrizayanti,; Zhang, Qianjing; Chen, Yuhong; Wang, Yupei; Zhang, Xuetian; Liu, Yang; Sun, Chao; Zhang, Hong; Hoheisel, Jörg D.

doi:10.1038/s41418-018-0231-3

Cited by 71 publications

(58 citation statements)

References 122 publications

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“…ASE is known to play a significant role in maintaining cellular physiology. Therefore, identifying the transcriptional splicing patterns may have the potential for early diagnosis, prognosis, and identification of therapeutic targets in tumor biology [50]. The nuclear hormone receptors, including estrogen and progesterone receptors, are known to modulate ASE.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

et al. 2020

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Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line antiandrogen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8–19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation and inhibition of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist-mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist-driven tumor invasion. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.

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Section: Discussionmentioning

confidence: 99%

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

et al. 2020

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“…Advances in RNA-targeted cancer therapies are being made which contribute to novel approaches for treating cancers affected by splicing factor mutations [ 134 ]. Strategies using ASOs to restore levels of affected proteins provide a compelling opportunity for future research in both cancer and other pathologies [ 135 , 136 ].…”

Section: Gbaf and Its Subunits In Mammalian Diseasementioning

confidence: 99%

GBAF, a small BAF sub-complex with big implications: a systematic review

Innis

Cabot

2020

Epigenetics & Chromatin

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ATP-dependent chromatin remodeling by histone-modifying enzymes and chromatin remodeling complexes is crucial for maintaining chromatin organization and facilitating gene transcription. In the SWI/SNF family of ATP-dependent chromatin remodelers, distinct complexes such as BAF, PBAF, GBAF, esBAF and npBAF/nBAF are of particular interest regarding their implications in cellular differentiation and development, as well as in various diseases. The recently identified BAF subcomplex GBAF is no exception to this, and information is emerging linking this complex and its components to crucial events in mammalian development. Furthermore, given the essential nature of many of its subunits in maintaining effective chromatin remodeling function, it comes as no surprise that aberrant expression of GBAF complex components is associated with disease development, including neurodevelopmental disorders and numerous malignancies. It becomes clear that building upon our knowledge of GBAF and BAF complex function will be essential for advancements in both mammalian reproductive applications and the development of more effective therapeutic interventions and strategies. Here, we review the roles of the SWI/SNF chromatin remodeling subcomplex GBAF and its subunits in mammalian development and disease.

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“…Such related studies have been reviewed elsewhere [3,4]. Additionally, relationships between alternative splicing and disease [5] or cancer [6,7] have received increasing attention. Understanding the pathogenesis associated with alternative splicing can shed light on diagnosis and therapy.…”

Section: Introductionmentioning

confidence: 99%

RNA-Seq Analysis Reveals Localization-Associated Alternative Splicing across 13 Cell Lines

Zeng

Hamada

2020

Genes

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Alternative splicing, a ubiquitous phenomenon in eukaryotes, is a regulatory mechanism for the biological diversity of individual genes. Most studies have focused on the effects of alternative splicing for protein synthesis. However, the transcriptome-wide influence of alternative splicing on RNA subcellular localization has rarely been studied. By analyzing RNA-seq data obtained from subcellular fractions across 13 human cell lines, we identified 8720 switching genes between the cytoplasm and the nucleus. Consistent with previous reports, intron retention was observed to be enriched in the nuclear transcript variants. Interestingly, we found that short and structurally stable introns were positively correlated with nuclear localization. Motif analysis reveals that fourteen RNA-binding protein (RBPs) are prone to be preferentially bound with such introns. To our knowledge, this is the first transcriptome-wide study to analyze and evaluate the effect of alternative splicing on RNA subcellular localization. Our findings reveal that alternative splicing plays a promising role in regulating RNA subcellular localization.

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Function, clinical application, and strategies of Pre-mRNA splicing in cancer

Cited by 71 publications

References 122 publications

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

GBAF, a small BAF sub-complex with big implications: a systematic review

RNA-Seq Analysis Reveals Localization-Associated Alternative Splicing across 13 Cell Lines

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