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Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells
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Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells

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SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Hironari Tamiya1, Hyungsoo Kim1, Oleksiy Klymenko2

  • 1Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.

The Journal of Clinical Investigation
|December 12, 2017
PubMed

Insights

SHARPIN regulates melanoma growth independently of LUBAC by activating PRMT5. This enhances PRMT5

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • SHARPIN is an adaptor protein for the linear ubiquitin chain assembly complex (LUBAC), known for its roles in NF-κB signaling and inflammation.
  • Melanoma is a significant form of skin cancer with complex regulatory pathways.
  • Protein arginine methyltransferase 5 (PRMT5) is implicated in various cellular processes, including cancer.

Purpose of the Study:

  • To investigate a potential LUBAC-independent role of SHARPIN in melanoma.
  • To elucidate the molecular mechanisms by which SHARPIN influences melanoma growth.
  • To identify novel therapeutic targets in melanoma treatment.

Main Methods:

  • Co-immunoprecipitation assays to study protein interactions.
  • Methyltransferase activity assays.
  • Western blotting and quantitative PCR to assess protein and gene expression.
  • Analysis of cancer patient data.

Main Results:

  • SHARPIN interacts with and enhances the activity of PRMT5, a type II protein arginine methyltransferase.
  • Activated PRMT5, via SHARPIN, regulates SOX10 and MITF expression by dimethylating transcription factors and inhibiting the transcriptional corepressor SKI.
  • SHARPIN-mediated PRMT5 activation counteracts inhibition by methylthioadenosine, which is co-deleted with CDKN2A in some cancers.
  • This SHARPIN-PRMT5 axis contributes to melanomagenesis through the SKI/SOX10 regulatory pathway.

Conclusions:

  • SHARPIN possesses a LUBAC-independent function in promoting melanoma growth.
  • The interaction between SHARPIN and PRMT5 is a key driver of melanomagenesis.
  • Targeting the SHARPIN-PRMT5-SKI/SOX10 axis may offer a novel therapeutic strategy for melanoma.
Keywords:
CancerCell BiologyMelanomaOncologySignal transduction

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