GREB1 : an evolutionarily conserved protein with a glycosyltransferase domain links ERα glycosylation and stability to cancer

• Main Authors: Shin, Eun Myoung, Huynh, Vinh Thang, Neja, Sultan Abda, Liu, Chia Yi, Raju, Anandhkumar, Tan, Kelly, Tan, Nguan Soon, Gunaratne, Jayantha, Bi, Xuezhi, Iyer, Lakshminarayan M., Aravind, L., Tergaonkar, Vinay
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2021
• Subjects: Science::Medicine; Bacteriophages; Cytology
• Online Access: https://hdl.handle.net/10356/151004
• Institution: Nanyang Technological University

What covalent modifications control the temporal ubiquitination of ERα and hence the duration of its transcriptional activity remain poorly understood. We show that GREB1, an ERα-inducible enzyme, catalyzes O-GlcNAcylation of ERα at residues T553/S554, which stabilizes ERα protein by inhibiting association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation of ERα results in reduced cellular ERα levels and insensitivity to estrogen. Higher GREB1 expression in ERα+ve breast cancer is associated with greater survival in response to tamoxifen, an ERα agonist. Mice lacking Greb1 exhibit growth and fertility defects reminiscent of phenotypes in ERα-null mice. In summary, this study identifies GREB1, a protein with an evolutionarily conserved domain related to DNA-modifying glycosyltransferases of bacteriophages and kinetoplastids, as the first inducible and the only other (apart from OGT) O-GlcNAc glycosyltransferase in mammalian cytoplasm and ERα as its first substrate.