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Significance FBXW7 is a typical tumor suppressor by targeting many oncoproteins for ubiquitylation and degradation, whereas LSD1 has oncogenic activity. Whether and how FBXW7 and LSD1 interact, with what biological consequence, are unknown. Here, we report that LSD1 is a pseudosubstrate of FBXW7. Upon binding with FBXW7, LSD1, instead of being degraded, disrupts FBXW7 dimerization and promotes FBXW7 self-ubiquitylation and degradation via proteasome and lysosomal pathways in a manner independent of its demethylase activity. As such, LSD1 abrogates biological functions of FBXW7 in growth suppression, nonhomologous end-joining repair, and radioprotection. Our study reveals a novel oncogenic mechanism of LSD1 by targeting FBXW7 and provides a sound strategy to reactivate FBXW7 by PROTAC-based LSD1 degradation in human cancers harboring wild-type FBXW7 with overexpressed LSD1.

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