The deubiquitinase USP9X regulates FBW7 stability and suppresses colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Gastroenterology

Background:

• The tumor suppressor FBW7 is crucial for targeting oncoproteins like c-MYC for degradation and is frequently mutated in human cancers.
• Loss of detectable FBW7 protein, despite intact mRNA, is observed in a significant proportion of colon cancers, suggesting post-transcriptional regulation.

Purpose of the Study:

• To elucidate the molecular mechanisms regulating FBW7 protein stability in colon cancer.
• To identify proteins that interact with and modulate FBW7 levels and function.

Main Methods:

• Proteomic analysis to identify FBW7 interactors.
• Ubiquitylation assays to assess FBW7 modification.
• Gene deletion studies in mice (Usp9x knockout).
• Analysis of intestinal phenotypes, regeneration, and tumor development.

Main Results:

• The deubiquitinase USP9X was identified as an FBW7 interactor that antagonizes FBW7 ubiquitylation.
• USP9X inactivation led to FBW7 destabilization and loss of its tumor-suppressive function.
• Mice lacking Usp9x in the gut exhibited reduced secretory cell differentiation, increased progenitor proliferation, impaired intestinal regeneration, and increased tumor burden in a colitis model.
• These phenotypes were partially rescued by c-Myc heterozygosity, implicating c-Myc as a key downstream effector.

Conclusions:

• USP9X acts as a crucial regulator of FBW7 protein stability through deubiquitylation, independent of FBW7 mutations.
• This USP9X-FBW7 axis represents a novel tumor suppressor mechanism in the mammalian intestine.
• Targeting USP9X or understanding its regulation of FBW7 could offer new therapeutic strategies for cancers with FBW7 dysregulation.