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

Lok Hang Chan1,2, Peihan Wang1,2, Shatha Abuhammad1,2

  • 1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Plos One
|November 2, 2023
PubMed

Insights

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors impact melanoma cell splicing distinctly from protein arginine methyltransferase 5 (PRMT5) inhibition, revealing unique therapeutic pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors show promise for melanoma treatment.
  • Protein arginine methyltransferase 5 (PRMT5) regulates alternative splicing downstream of CDK4/6.
  • The precise impact of CDK4/6 inhibition on melanoma splicing and its PRMT5 dependence requires clarification.

Purpose of the Study:

  • To investigate the full effects of CDK4/6 inhibition on melanoma splicing events.
  • To determine the extent to which these splicing events are dependent on PRMT5.
  • To compare the distinct and common RNA splicing and gene expression profiles induced by CDK4/6 and PRMT5 inhibition.

Main Methods:

  • Utilized full-length mRNA sequencing on CHL1 and A375 melanoma cell lines.
  • Treated cell lines with the CDK4/6 inhibitor palbociclib and the PRMT5 inhibitor GSK3326595.
  • Analyzed data for differential gene expression and differential pre-mRNA splicing.

Main Results:

  • PRMT5 inhibition induced more extensive changes in gene expression and RNA splicing than CDK4/6 inhibition.
  • Both PRMT5 and CDK4/6 inhibition shared common RNA splicing events and gene expression profiles.
  • The majority of RNA splicing events induced by CDK4/6 inhibition were distinct from those induced by PRMT5 inhibition.

Conclusions:

  • CDK4/6 regulates alternative splicing independently of PRMT5.
  • CDK4/6 inhibition leads to divergent gene expression changes compared to PRMT5 inhibition.
  • These findings highlight distinct therapeutic mechanisms for CDK4/6 and PRMT5 inhibitors in melanoma.

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