KEAP1 Mutations Drive Tumorigenesis by Suppressing SOX9 Ubiquitination and Degradation

Area of Science:

• Molecular Biology
• Cancer Biology
• Biochemistry

Background:

• SOX9 amplification is common in advanced human cancers.
• SOX9 protein stability is regulated by ubiquitination-dependent proteasome degradation.
• The precise molecular mechanisms controlling SOX9 degradation are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms regulating SOX9 protein stability.
• To investigate the role of KEAP1 in SOX9 degradation.
• To explore therapeutic strategies targeting SOX9 stability in cancer.

Main Methods:

• Investigated the interaction between KEAP1 and SOX9.
• Utilized loss-of-function mutations in KEAP1 and SOX9.
• Examined the effect of CKIγ-mediated phosphorylation on KEAP1/SOX9 interaction.
• Assessed the impact of DNA damage drugs (topoisomerase inhibitors) on KEAP1/SOX9 interaction and degradation.

Main Results:

• KEAP1, a Cullin 3-based ubiquitin ligase, targets SOX9 for proteasome-mediated degradation.
• Loss-of-function mutations in KEAP1 impair SOX9 polyubiquitination and degradation, increasing SOX9 levels and promoting tumorigenesis.
• Mutations or truncations in SOX9 affecting ubiquitination sites (e.g., K249R mutation) enhance protein stability.
• CKIγ-mediated phosphorylation modulates the KEAP1/SOX9 interaction.
• DNA damage drugs activate CKI, restoring KEAP1/SOX9 interaction and SOX9 degradation.

Conclusions:

• KEAP1 negatively regulates SOX9 protein stability, thereby controlling tumorigenesis.
• KEAP1 mutations that compromise SOX9 degradation contribute to cancer development.
• Targeting SOX9 resistance to KEAP1-mediated degradation offers a potential therapeutic strategy for cancers with KEAP1 mutations.