Histone Demethylase LSD2 Acts as an E3 Ubiquitin Ligase and Inhibits Cancer Cell Growth through Promoting Proteasomal Degradation of OGT

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 of LSD2 stabilizes OGT and promotes colony formation of 293T cells. LSD2 regulates distinct groups of target genes through histone demethylase and E3 ligase activities, respectively. Such regulation suggests a mechanism through which LSD2 suppresses tumorigenesis by promoting the degradation of OGT and other substrates yet to be discovered. Our study reveals an antigrowth function of LSD2 dependent on its E3 ligase activity and establishes a connection between histone demethylase and ubiquitin-dependent pathway.

A JUMONJI Protein with E3 Ligase and Histone H3 Binding Activities Affects Transposon Silencing in Arabidopsis

“…There is precedent for the combination of histone demethylation and E3 ligase activity. Recently, the animal histone demethylase LSD2 implicated in cancer cell growth has been found to have E3 ubiquitin ligase activity toward O-GlcNAc transferase (Yang et al, 2015). JMJ24 shares the RING domains with numerous KDM3 clade members (Zhou and Ma, 2008;Aiese Cigliano et al, 2013).…”

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…In contrast to KDM1A, KDM1B does not contain the Tower domain but rather contains a zinc-finger area at its N-terminal region ( Figure 2B). This zinc-finger domain or SWIRM motif is indispensable for its demethylation activity [53,54]. Genome-wide studies have demonstrated that KDM1B is bound mainly within gene bodies of highly transcribed genes and is almost completely absent from gene promoters [55].…”

“…Indeed, this enzyme is mainly expressed in oocytes, where, through its H3K4 demethylation activity, it enables de novo DNA methylation in several imprinted genes (genes expressed in a parent-of-origin-specific manner) [58]. Finally, KDM1B inhibits lung cancer cell growth independently from its demethylase activity [54]. The zinc finger domain of KDM1B catalyzes the ubiquitylation of O-GlcNAc transferase (OGT) and induces its degradation.…”

“…The zinc finger domain of KDM1B catalyzes the ubiquitylation of O-GlcNAc transferase (OGT) and induces its degradation. OGT degradation, in turn, reduces oncogene expression and promotes tumor cell growth [54]. The finding that the histone demethylases KDM1B has E3 ligase activity raises the question of a possible connection between histone demethylase and ubiquitin-dependent pathway.…”

“…Through its polyubiquitylation of the O-GlcNAc transferase OGT, KDM1B induces the OGT proteasomal degradation. OGT is often upregulated in cancer, and loss of KDM1B E3 ligase activity leads to activation of different classes of oncogenes, demonstrating that KDM1B may act as a suppressor of tumorigenesis through its E3 ligase activity and its effects on OGT stability [54].…”