LSD1 Demethylase and the Methyl-Binding Protein PHF20L1 Prevent SET7 Methyltransferase–Dependent Proteolysis of the Stem-Cell Protein SOX2
Document Type
Article
Publication Date
3-9-2018
Publication Title
Journal of Bological Chemistry
Volume
293
Issue
10
First page number:
3663
Last page number:
3674
Abstract
The pluripotency-controlling stem-cell protein SRY-box 2 (SOX2) plays a pivotal role in maintaining the self-renewal and pluripotency of embryonic stem cells and also of teratocarcinoma or embryonic carcinoma cells. SOX2 is monomethylated at lysine 119 (Lys-119) in mouse embryonic stem cells by the SET7 methyltransferase, and this methylation triggers ubiquitin-dependent SOX2 proteolysis. However, the molecular regulators and mechanisms controlling SET7-induced SOX2 proteolysis are unknown. Here, we report that in human ovarian teratocarcinoma PA-1 cells, methylation-dependent SOX2 proteolysis is dynamically regulated by the LSD1 lysine demethylase and a methyl-binding protein, PHD finger protein 20–like 1 (PHF20L1). We found that LSD1 not only removes the methyl group from monomethylated Lys-117 (equivalent to Lys-119 in mouse SOX2), but it also demethylates monomethylated Lys-42 in SOX2, a reaction that SET7 also regulated and that also triggered SOX2 proteolysis. Our studies further revealed that PHF20L1 binds both monomethylated Lys-42 and Lys-117 in SOX2 and thereby prevents SOX2 proteolysis. Down-regulation of either LSD1 or PHF20L1 promoted SOX2 proteolysis, which was prevented by SET7 inactivation in both PA-1 and mouse embryonic stem cells. Our studies also disclosed that LSD1 and PHF20L1 normally regulate the growth of pluripotent mouse embryonic stem cells and PA-1 cells by preventing methylation-dependent SOX2 proteolysis. In conclusion, our findings reveal an important mechanism by which the stability of the pluripotency-controlling stem-cell protein SOX2 is dynamically regulated by the activities of SET7, LSD1, and PHF20L1 in pluripotent stem cells.
Keywords
Ubiquitin-dependent protease; Stem cells; Cancer stem cells; Pluripotency; Post-translational modification (PTM); LSD1; Methylation; PHF20L1; SET7; SOX2
Language
English
Repository Citation
Zhang, C.,
Hoang, N.,
Leng, F.,
Saxena, L.,
Lee, L.,
Alejo, S.,
Qi, D.,
Khal, A.,
Sun, H.,
Lu, F.,
Zhang, H.
(2018).
LSD1 Demethylase and the Methyl-Binding Protein PHF20L1 Prevent SET7 Methyltransferase–Dependent Proteolysis of the Stem-Cell Protein SOX2.
Journal of Bological Chemistry, 293(10),
3663-3674.
http://dx.doi.org/10.1074/jbc.RA117.000342