Spliceosomal vulnerability of MYCN-amplified neuroblastoma is contingent on PRMT5-mediated regulation of epitranscriptomic and metabolomic pathways
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View abstract on PubMed
Summary
This summary is machine-generated.Targeting PRMT5 with GSK3203591 inhibits MYCN-amplified neuroblastoma by disrupting splicing, epitranscriptomics, and glutamine metabolism, offering a new therapeutic strategy.
Area Of Science
- Oncology
- Molecular Biology
- Biochemistry
Background
- MYCN over-expression drives approximately 50% of poor-prognosis neuroblastomas.
- PRMT5 protein interacts with MYCN, and its knockdown induces apoptosis in MYCN-amplified (MNA) neuroblastoma cells.
Purpose Of The Study
- To evaluate the efficacy of the PRMT5 inhibitor GSK3203591 and its in vivo analogue GSK3326593 as targeted therapeutics for MNA neuroblastoma.
- To elucidate the molecular mechanisms underlying the sensitivity of MNA neuroblastoma to PRMT5 inhibition.
Main Methods
- Cell-line analyses and RNA sequencing of MNA neuroblastoma treated with GSK3203591.
- Stable isotope labeling to assess glutamine metabolism.
- In vivo efficacy studies using Th-MYCN mice.
Main Results
- GSK3203591 induced MYCN-dependent growth inhibition and apoptosis, with MNA neuroblastoma lines showing ~200-fold greater sensitivity.
- Treatment revealed deregulated MYCN transcriptional programs, altered mRNA splicing, and impeded glutamine metabolism.
- GSK3203591 treatment decreased glutaminase (GLS) protein by affecting METTL3 and YTHDF3 expression via splicing alterations, impacting GLS mRNA m6A methylation.
Conclusions
- MNA neuroblastoma exhibits PRMT5-dependent vulnerability related to spliceosomal function.
- The epitranscriptome and glutamine metabolism are critical determinants of MNA neuroblastoma sensitivity to PRMT5 inhibition.
- GSK3203591 and GSK3326593 demonstrate therapeutic potential for MNA neuroblastoma.
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