LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• FBXW7 is a tumor suppressor that targets oncoproteins for degradation.
• Lysine-specific demethylase 1 (LSD1) is known as a histone demethylase, but its other functions are unclear.

Purpose of the Study:

• To investigate the potential demethylase-independent activity of LSD1.
• To elucidate the mechanism by which LSD1 interacts with and affects FBXW7.

Main Methods:

• Co-immunoprecipitation assays to confirm LSD1-FBXW7 binding.
• Ubiquitylation assays to assess FBXW7 modification.
• Western blotting and proteasome/lysosome inhibitors to study FBXW7 degradation.
• Cellular assays to evaluate the biological impact on growth suppression, DNA repair, and radiosensitivity.

Main Results:

• LSD1 directly binds to FBXW7, independent of its demethylase activity.
• LSD1 binding prevents FBXW7 dimerization, promoting FBXW7 self-ubiquitylation and subsequent degradation.
• LSD1-mediated FBXW7 destabilization impairs tumor suppressor functions, including growth inhibition and DNA repair.
• Degradation of FBXW7 is dependent on the autophagy protein p62/SQSTM1.

Conclusions:

• LSD1 possesses a novel, demethylase-independent function in destabilizing the tumor suppressor FBXW7.
• This interaction contributes to oncogenesis by abrogating FBXW7's tumor-suppressive roles.
• Targeting the LSD1 protein, not just its enzymatic activity, presents a potential new strategy for anticancer drug development.