Modulation of<i>MKNK2</i>alternative splicing by splice-switching oligonucleotides as a novel approach for glioblastoma treatment

Mogilevsky, Maxim; Shimshon, Odelia; Kumar, Saran; Mogilevsky, Adi; Keshet, Eli; Yavin, Eylon; Heyd, Florian; Karni, Rotem

doi:10.1093/nar/gky921

Cited by 58 publications

(44 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Alternative selection of the two last exons in the MNK2 kinase gene (MKNK2) yields either the MNK2a variant, which displays tumor suppressor activity, or the pro-oncogenic MNK2b variant. In vivo delivery of an SSO that efficiently promotes splicing of MNK2a inhibited GBM growth and sensitized GBM cells to chemotherapeutic agents [129]. Comparable anti-cancer results were obtained by employing the same strategy to promote splicing of a truncated inactive telomerase subunit (hTERT).…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

View full text Add to dashboard Cite

Brain tumors are a heterogeneous group of neoplasms ranging from almost benign to highly aggressive phenotypes. The malignancy of these tumors mostly relies on gene expression reprogramming, which is frequently accompanied by the aberrant regulation of RNA processing mechanisms. In brain tumors, defects in alternative splicing result either from the dysregulation of expression and activity of splicing factors, or from mutations in the genes encoding splicing machinery components. Aberrant splicing regulation can generate dysfunctional proteins that lead to modification of fundamental physiological cellular processes, thus contributing to the development or progression of brain tumors. Herein, we summarize the current knowledge on splicing abnormalities in brain tumors and how these alterations contribute to the disease by sustaining proliferative signaling, escaping growth suppressors, or establishing a tumor microenvironment that fosters angiogenesis and intercellular communications. Lastly, we review recent efforts aimed at developing novel splicing-targeted cancer therapies, which employ oligonucleotide-based approaches or chemical modulators of alternative splicing that elicit an impact on brain tumor biology.

show abstract

Section: Therapeutic Approachesmentioning

confidence: 99%

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

View full text Add to dashboard Cite

show abstract

“…For example, Barbagallo et al found that circSMARCA5 negatively regulated splicing of VEGFA through splicing factor SRSF1, which exerted antiangiogenic function . Mogilevsky et al discovered that the manipulation of MKNK2 AS significantly suppressed the oncogenic properties of GBM cells and resensitized the cells to chemotherapy, which suggested a novel treatment strategy for clinical practice . However, the literature primarily focuses on one AS and is lacking an exhaustive overview of all splicing events.…”

Section: Introductionmentioning

confidence: 99%

“…21 Mogilevsky et al discovered that the manipulation of MKNK2 AS significantly suppressed the oncogenic properties of GBM cells and resensitized the cells to chemotherapy, which suggested a novel treatment strategy for clinical practice. 22 However, the literature primarily focuses on one AS and is lacking an exhaustive overview of all splicing events. In Sadeque's study, the prognostic value of alternative exon usage, a broad category of AS, was comprehensively investigated in GBM patients.…”

Section: Introductionmentioning

confidence: 99%

Role of alternative splicing signatures in the prognosis of glioblastoma

Xie

Dang

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

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.

show abstract

“…However, oligonucleotides are well suited to modulate mRNA splicing since they bind with high selectivity directly to the disease-causing element. Consequently, there is considerable excitement for a wave of SSOs that are currently in pre-clinical and clinical development (32,(60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria

Halloy

Iyer

Ćwiek

et al. 2020

Preprint

View full text Add to dashboard Cite

ABSTRACTErythropoietic protoporphyria (EPP) is a rare genetic disease in which patients experience acute phototoxic reactions after sunlight exposure. It is caused by a deficiency in ferrochelatase (FECH) in the heme biosynthesis pathway. Most patients exhibit a loss-of-function mutation in trans to an allele bearing a SNP that favours aberrant splicing of transcripts. One viable strategy for EPP is to deploy splice-switching oligonucleotides (SSOs) to increase FECH synthesis, whereby an increase of a few percent would provide therapeutic benefit. However, successful application of SSOs in bone marrow cells is not described. Here, we show that SSOs comprising methoxyethyl-chemistry increase FECH levels in cells. We conjugated one SSO to three prototypical targeting groups and administered them to a mouse model of EPP in order to study their biodistribution, their metabolic stability and their FECH splice-switching ability. The SSOs exhibited distinct distribution profiles, with increased accumulation in liver, kidney, bone marrow and lung. However, they also underwent substantial metabolism, mainly at their linker groups. An SSO bearing a cholesteryl group increased levels of correctly spliced FECH transcript by 80% in the bone marrow. The results provide a promising approach to treat EPP and other disorders originating from splicing dysregulation in the bone marrow.

show abstract

Modulation ofMKNK2alternative splicing by splice-switching oligonucleotides as a novel approach for glioblastoma treatment

Cited by 58 publications

References 36 publications

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Role of alternative splicing signatures in the prognosis of glioblastoma

Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria

Contact Info

Product

Resources

About