Aberrant RNA Splicing in Cancer and Drug Resistance

Wang, Bi-Dar; Lee, Norman H.

doi:10.3390/cancers10110458

Cited by 141 publications

(119 citation statements)

References 203 publications

(262 reference statements)

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“…The spliceosome, consisting of five small nuclear RNAs (U1, U2, U4, U5, and U6) and abundant protein factors, is the place where AS happens . Splicing factors are a core protein in the spliceosome, playing pivotal roles in regulating the splicing process.…”

Section: Discussionmentioning

confidence: 99%

Role of alternative splicing signatures in the prognosis of glioblastoma

Xie

Dang

et al. 2019

Cancer Medicine

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Background Increasing evidence has validated the crucial role of alternative splicing (AS) in tumors. However, comprehensive investigations on the entirety of AS and their clinical value in glioblastoma (GBM) are lacking. Methods The AS profiles and clinical survival data related to GBM were obtained from The Cancer Genome Atlas database. Univariate and multivariate Cox regression analyses were performed to identify survival‐associated AS events. A risk score was calculated, and prognostic signatures were constructed using seven different types of independent prognostic AS events, respectively. The Kaplan‐Meier estimator was used to display the survival of GBM patients. The receiver operating characteristic curve was applied to compare the predictive efficacy of each prognostic signature. Enrichment analysis and protein interactive networks were conducted using the gene symbols of the AS events to investigate important processes in GBM. A splicing network between splicing factors and AS events was constructed to display the potential regulatory mechanism in GBM. Results A total of 2355 survival‐associated AS events were identified. The splicing prognostic model revealed that patients in the high‐risk group have worse survival rates than those in the low‐risk group. The predictive efficacy of each prognostic model showed satisfactory performance; among these, the Alternate Terminator (AT) model showed the best performance at an area under the curve (AUC) of 0.906. Enrichment analysis uncovered that autophagy was the most enriched process of prognostic AS gene symbols in GBM. The protein network revealed that UBC, VHL, KCTD7, FBXL19, RNF7, and UBE2N were the core genes in GBM. The splicing network showed complex regulatory correlations, among which ELAVL2 and SYNE1_AT_78181 were the most correlated (r = −.506). Conclusions Applying the prognostic signatures constructed by independent AS events shows promise for predicting the survival of GBM patients. A splicing regulatory network might be the potential splicing mechanism in GBM.

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Section: Discussionmentioning

confidence: 99%

Role of alternative splicing signatures in the prognosis of glioblastoma

Xie

Dang

et al. 2019

Cancer Medicine

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“…It is estimated that ∼95% of human genes are alternatively spliced through differences in the way exons are joined [2], thus greatly increasing the complexity of the proteome by producing multiple mature mRNA transcripts from the same gene [2]. Under normal conditions, alternative splicing is tightly regulated, but changes in alternative splicing are increasingly linked to a variety of human diseases, and in particular to cancer [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Structural and functional characterisation of human RNA helicase DHX8 provides insights into the mechanism of RNA-stimulated ADP release

Felisberto‐Rodrigues

Thomas

McAndrew

et al. 2019

Biochemical Journal

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DHX8 is a crucial DEAH-box RNA helicase involved in splicing and required for the release of mature mRNA from the spliceosome. Here, we report the biochemical characterisation of full-length human DHX8 and the catalytically active helicase core DHX8Δ547, alongside crystal structures of DHX8Δ547 bound to ADP and a structure of DHX8Δ547 bound to poly(A)6 single-strand RNA. Our results reveal that DHX8 has an in vitro binding preference for adenine-rich RNA and that RNA binding triggers the release of ADP through significant conformational flexibility in the conserved DEAH-, P-loop and hook-turn motifs. We demonstrate the importance of R620 and both the hook-turn and hook-loop regions for DHX8 helicase activity and propose that the hook-turn acts as a gatekeeper to regulate the directional movement of the 3′ end of RNA through the RNA-binding channel. This study provides an in-depth understanding of the activity of DHX8 and contributes insights into the RNA-unwinding mechanisms of the DEAH-box helicase family.

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“…Notably, the PGC-1a family of transcriptional coactivators is composed of an expanding list of transcript isoforms generated by multiple promoters and alternative pre-mRNA splicing, and these resulting protein variants are known to display unique functional properties (Martínez-Redondo et al, 2016;Martínez-Redondo et al, 2015). Rare, alternatively spliced transcripts such as PGC-1a4 are emerging as key players in multiple cancer types and thus represent an attractive target for pharmacological intervention (Kimes et al, 2014;Oltean and Bates, 2014;Wang and Lee, 2018;Zhang and Manley, 2013). To date however, the specific role of PGC-1a alternative splice variants in cancer has remained elusive.…”

Section: Discussionmentioning

confidence: 99%

CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

Musicant

Parag-Sharma

Gong

et al. 2020

Preprint

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Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1a splice variant PGC-1a4, which regulates PPARg-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARg inhibition with inverse agonists.These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy.

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Aberrant RNA Splicing in Cancer and Drug Resistance

Cited by 141 publications

References 203 publications

Role of alternative splicing signatures in the prognosis of glioblastoma

Role of alternative splicing signatures in the prognosis of glioblastoma

Structural and functional characterisation of human RNA helicase DHX8 provides insights into the mechanism of RNA-stimulated ADP release

CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

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