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NSD3S stabilizes MYC through hindering its interaction with FBXW7

Valentina Gonzalez-Pecchi1,2, Albert K Kwan2, Sean Doyle2

  • 1Graduate Program in Cancer Biology, Emory University, Atlanta, GA, USA.

Journal of Molecular Cell Biology
|October 23, 2019
PubMed

Insights

The nuclear receptor binding SET domain protein 3 short isoform (NSD3S) stabilizes the MYC oncoprotein by blocking its degradation. This mechanism reveals a new pathway for NSD3S

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The MYC transcription factor is crucial for cell growth and its enhanced stability promotes cancer.
  • Nuclear receptor binding SET domain protein 3 (NSD3), particularly its NSD3S isoform, has been identified as a MYC modulator.
  • The precise mechanism by which NSD3S stabilizes MYC and contributes to oncogenesis is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which the NSD3S isoform stabilizes MYC.
  • To characterize the binding interface between NSD3S and MYC.
  • To investigate how NSD3S binding affects MYC degradation pathways.

Main Methods:

  • Protein-protein interaction analysis to define the binding interface between NSD3S and MYC.
  • Biochemical assays to assess the impact of NSD3S on MYC stability and degradation.
  • Investigation of the role of FBXW7 (F-box and WD repeat domain containing 7) in NSD3S-mediated MYC regulation.

Main Results:

  • The binding interface between NSD3S and MYC was narrowed to a 15-amino acid region in NSD3S.
  • NSD3S binds to MYC and disrupts the interaction between MYC and the E3 ubiquitin ligase FBXW7.
  • This disruption inhibits FBXW7-mediated proteasomal degradation of MYC, leading to increased MYC protein half-life and stability.

Conclusions:

  • NSD3S stabilizes MYC by preventing its degradation via the FBXW7-mediated pathway.
  • This novel mechanism highlights NSD3S's oncogenic function in promoting MYC stability.
  • Understanding this interaction provides insights into MYC-driven tumorigenesis and potential therapeutic strategies.
Keywords:
FBXW7MYCNSD3Scancerprotein–protein interaction

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