Mol Cell. 2015 Apr 2;58(1):47-59. doi: 10.1016/j.molcel.2015.01.038. Epub 2015 Mar 12.

Histone Demethylase LSD2 Acts as an E3 Ubiquitin Ligase and Inhibits 

Cancer Cell Growth through Promoting Proteasomal Degradation of OGT

Yang Y¹, Yin X¹, Yang H¹, Xu Y².

Abstract

Histone demethylases play important roles in various biological processes in a manner dependent on their demethylase activities. However, little is known about their demethylase-independent activities. Here, we report that LSD2, a well-known histone H3K4me1/me2 demethylase, possesses an unexpected E3 ubiquitin ligase activity. LSD2 directly ubiquitylates and promotes proteasome-dependent degradation of O-GlcNAc transferase (OGT), and inhibits A549 lung cancer cell growth in a manner dependent on its E3 ligase activity, but not demethylase activity. The depletion ofLSD2 stabilizes OGT and promotes colony formation of 293T cells. LSD2 regulates distinct groups of target genes through histone demethylaseand E3 ligase activities, respectively. Such regulation suggests a mechanism through which LSD2 suppresses tumorigenesis by promoting thedegradation of OGT and other substrates yet to be discovered. Our study reveals an antigrowth function of LSD2 dependent on its E3 ligaseactivity and establishes a connection between histone demethylase and ubiquitin-dependent pathway.

文章链接：http://www.sciencedirect.com/science/article/pii/S1097276515000714