The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation

• Type of Material: Article
• Authors: Chandra M. Das, University of Texas; Pete Taylor, University of Texas; Monica Gireud, University of Texas; Akanksha Singh, University of Texas; Dean Lee, University of Texas; Greg Fuller, University of Texas; Lingyun Ji, University of Texas; Jason Fangusaro, Emory University; Veena Rajaram, Northwestern University; Stewart Goldman, Northwestern University; Charles Eberhart, Johns Hopkins University; Vidya Gopalakrishnan, University of Texas
• Language: English
• Date: 2013-03-28
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Macmillan Publishers Limited All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2012.182
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 32
• Issue: 13
• Start Page: 1691
• End Page: 1701
• Grant/Funding Information: This work was supported by grants from the American Cancer Center (RSG-09-273-01-DDC) and the National Institutes of Neurological Disorders and Stroke (1R03NS077021-01) to VG.
• Keywords: p27; Science & Technology; Oncology; NEURONAL DIFFERENTIATION; USP37; NEURAL DEVELOPMENT; REST; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; deubiquitylase; TUMOR SUPPRESSORS; CDK INHIBITOR P27; N-MYC; SCF-BETA-TRCP; ONCOGENIC TRANSFORMATION; Cell Biology; RESTRICTIVE SILENCER FACTOR; SUBTYPE SPECIFICATION; Genetics & Heredity; proliferation; REGULATES PROTEOLYSIS
• Research Categories: Health Sciences, Oncology; Biology, Neuroscience

Abstract

The RE1 silencing transcription factor (REST) is a repressor of neuronal differentiation and its elevated expression in neural cells blocks neuronal differentiation. In this study, we demonstrate a role for REST in the control of proliferation of medulloblastoma cells. REST expression decreased the levels of cyclin-dependent kinase (CDK)NIB/p27, a CDK inhibitor and a brake of cell proliferation in these cells. The reciprocal relationship between REST and p27 was validated in human tumor samples. REST knockdown in medulloblastoma cells derepessed a novel REST target gene encoding the deubiquitylase ubiquitin (Ub)-specific peptidase 37 (USP37). Ectopically expressed wild-type USP37 formed a complex with p27, promoted its deubiquitination and stabilization and blocked cell proliferation. Knockdown of REST and USP37 prevented p27 stabilization and blocked the diminution in proliferative potential that normally accompanied REST loss. Unexpectedly, wild-type USP37 expression also induced the expression of REST-target neuronal differentiation genes even though REST levels were unaffected. In contrast, a mutant of USP37 carrying a site-directed change in a conserved cysteine failed to rescue REST-mediated p27 destabilization, maintenance of cell proliferation and blockade to neuronal differentiation. Consistent with these findings, a significant correlation between USP37 and p27 was observed in patient tumors. Collectively, these findings provide a novel connection between REST and the proteasomal machinery in the control of p27 and cell proliferation in medulloblastoma cells.