NSD3S stabilizes MYC through hindering its interaction with FBXW7

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.