Sustained cancer-relevant alternative RNA splicing events driven by PRMT5 in high-risk neuroblastoma.
Laurel Tabe Bate-EyaGulsah AlbayrakSimon Mark CarrAmit ShresthaAlexander KanapinAnastasia SamsonovaNicholas Barrie La ThanguePublished in: Molecular oncology (2024)
Protein arginine methyltransferase 5 (PRMT5) is over-expressed in a wide variety of cancers and is implicated as having a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1. We investigated the relevance of PRMT5 and E2F1 in neuroblastoma (NB) and found that elevated expression of PRMT5 and E2F1 occurs in poor prognosis high-risk disease and correlates with an amplified Myelocytomatosis viral-related oncogene, neuroblastoma-derived (MYCN) gene. Our results show that MYCN drives the expression of splicing factor genes that, together with PRMT5 and E2F1, lead to a deregulated alternative RNA splicing programme that impedes apoptosis. Pharmacological inhibition of PRMT5 or inactivation of E2F1 restores normal splicing and renders NB cells sensitive to apoptosis. Our findings suggest that a sustained cancer-relevant alternative RNA splicing programme desensitises NB cells to apoptosis, and identify PRMT5 as a potential therapeutic target for high-risk disease.
Keyphrases
- poor prognosis
- cell cycle arrest
- induced apoptosis
- cell death
- endoplasmic reticulum stress
- long non coding rna
- oxidative stress
- pi k akt
- papillary thyroid
- transcription factor
- genome wide
- nitric oxide
- binding protein
- study protocol
- squamous cell carcinoma
- gene expression
- signaling pathway
- climate change
- amino acid
- risk assessment
- nucleic acid
- human health