title: 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.
authors.affiliation: Fudan University Shanghai Cancer Center, Department of Oncology, and Institutes of Biomedical Sciences and School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Fudan University Shanghai Cancer Center, Department of Oncology, and Institutes of Biomedical Sciences and School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Yin
authors.affiliation: Fudan University Shanghai Cancer Center, Department of Oncology, and Institutes of Biomedical Sciences and School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Huirong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Fudan University Shanghai Cancer Center, Department of Oncology, and Institutes of Biomedical Sciences and School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China. Electronic address: xuyh@fudan.edu.cn.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Xu
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D006657:Histones; D056466:Histone Demethylases; C000595993:KDM1B protein, human; D044767:Ubiquitin-Protein Ligases; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D046988:Proteasome Endopeptidase Complex