PRMT5 and CDK4/6 inhibition result in distinctive patterns of alternative splicing in melanoma

Drugs targeting cyclin-dependent kinases 4 and 6 (CDK4/6) are promising new treatments for melanoma and other solid malignancies. In studies on CDK4/6 inhibitor resistance, protein arginine methyltransferase 5 (PRMT5) regulation of alternative splicing was shown to be an important downstream compone...

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Published in:PloS one 2023-11, Vol.18 (11), p.e0292278-e0292278
Main Authors: Chan, Lok Hang, Wang, Peihan, Abuhammad, Shatha, Lim, Lydia Rui Jia, Cursons, Joseph, Sheppard, Karen E, Goode, David L
Format: Article
Language:English
Subjects:
Alternative splicing
Biology and life sciences
Cancer
Cancer cells
Care and treatment
Cell cycle
Cell lines
Cyclin-dependent kinase 4
Cyclin-dependent kinases
Diagnosis
Drug delivery
Drug dosages
Gene expression
Gene sequencing
Genes
Genomes
Health aspects
Inhibition
Kinases
Malignancy
Medicine and Health Sciences
Melanoma
Messenger RNA
Protein arginine methyltransferase
Research and Analysis Methods
Ribonucleic acid
RNA
RNA sequencing
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Summary:Drugs targeting cyclin-dependent kinases 4 and 6 (CDK4/6) are promising new treatments for melanoma and other solid malignancies. In studies on CDK4/6 inhibitor resistance, protein arginine methyltransferase 5 (PRMT5) regulation of alternative splicing was shown to be an important downstream component of the CDK4/6 pathway. However, the full effects of inhibition of CDK4/6 on splicing events in melanoma and the extent to which they are dependent on PRMT5 has not been established. We performed full-length mRNA sequencing on CHL1 and A375 melanoma cell lines treated with the CDK4/6 inhibitor palbociclib and the PRMT5 inhibitor GSK3326595 and analysed data for differential gene expression and differential pre-mRNA splicing induced by these agents. Changes in gene expression and RNA splicing were more extensive under PRMT5 inhibition than under CDK4/6 inhibition. Although PRMT5 inhibition and CDK4/6 inhibition induced common RNA splicing events and gene expression profiles, the majority of events induced by CDK4/6 inhibition were distinct. Our findings indicate CDK4/6 has the ability to regulate alternative splicing in a manner that is distinct from PRMT5 inhibition, resulting in divergent changes in gene expression under each therapy.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0292278