LSD1 Destabilizes FBXW7 Independent of Its Demethylase Activity

Abstract

FBXW7 acts as a typical tumor suppressor, with loss of function alterations in human cancers, by promoting ubiquitylation and degradation of many oncoproteins. Lysine-specific demethylase 1 (LSD1) is a well-characterized histone demethylase. Whether LSD1 has demethylase-independent activity remains elusive. Here we report that LSD1 directly binds to FBXW7 to destabilize FBXW7 independent of its demethylase activity. Specifically, LSD1 is a pseudo-substrate of FBXW7 and LSD1-FBXW7 binding does not trigger LSD1 ubiquitylation, instead promote FBXW7 self-ubiquitylation by preventing FBXW7 dimerization. The self-ubiquitylated FBXW7 is subjected to degradation by proteasome and lysosome in a manner dependent of autophagy protein p62/SQSTM1. Biologically, LSD1 destabilizes FBXW7 to abrogate its functions in growth suppression, NHEJ repair and radioprotection. Collectively, our study revealed a previously unknown activity of LSD1, which likely contributes to its oncogenic function. Targeting LSD1 protein, rather than its demethylase activity, might be a unique approach for LSD1-based drug discovery for anti-cancer application.