Abstract
LSD1 is a histone lysine demethylase, which is highly expressed in multiple types of human cancer. Although its roles in transcriptional regulation have been well-studied, functional regulation of LSD1 by post-translational modifications still remains unknown. Here, we demonstrate that the histone lysine methyltransferase SUV39H2 trimethylated LSD1 on lysine 322. Knockdown of SUV39H2 resulted in a decrease of LSD1 protein even though the mRNA levels were unchanged. SUV39H2-induced LSD1 methylation suppresses LSD1 polyubiquitination and subsequent degradation. In addition, we also observed indirect effect of SUV39H2 overexpression on LSD1-target genes. Our results reveal the regulatory mechanism of LSD1 protein through its lysine methylation by SUV39H2 in human cancer cells.
Highlights
LSD1, the first-identified histone lysine-specific demethylase [1], is an amine oxidase that catalyzes lysine demethylation in a flavin adenine dinucleotide (FAD)dependent oxidative reaction
We validated the methylation of LSD1 by SUV39H2 in 293T cells that were transfected with a FLAG-LSD1 wild-type (WT) vector or a FLAGLSD1-K322R vector together with an HA-SUV39H2
We identified that LSD1 was trimethylated by SUV39H2 at lysine 322, and that SUV39H2-mediated LSD1 methylation stabilized the protein levels of LSD1 through inhibition of its polyubiquitination
Summary
LSD1 ( known as KDM1A, AOF2, and BHC110), the first-identified histone lysine-specific demethylase [1], is an amine oxidase that catalyzes lysine demethylation in a flavin adenine dinucleotide (FAD)dependent oxidative reaction. It was reported that LSD1 demethylates lysine residues at non-histone proteins including p53, MYPT1, DNMT1 and E2F1 [7,8,9,10]. LSD1 demethylates p53 at lysine 370 and represses p53-mediated transcriptional upregulation including induction of apoptosis [8, 11, 12]. LSD1 was found as a member of multiple complexes including a CoREST complex and a NuRD complex, both of which function in transcription repression [1315]. Depletion of LSD1 inhibits cancer cell proliferation [16]. These results suggested that LSD1 could be a promising therapeutic target for development of drugs to treat cancers. Other modifications influencing functions of LSD1 have not been elucidated, so far
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