title: Stabilization of LSD1 by deubiquitinating enzyme USP7 promotes glioblastoma cell tumorigenesis and metastasis through suppression of the p53 signaling pathway.
abstract: The substrates and mechanisms of ubiquitin specific peptidase 7 (USP7) in glioma remain unclear. Lysine‑specific demethylase 1 (LSD1) may undergo proteasomal degradation; however, a reciprocal mechanism that stabilizes LSD1 in glioma has not been dertermined. Here co-immunoprecipitation and GST pull-down assays revealed that LSD1 is associated with USP7 in vivo and in vitro. USP7 inhibited LSD1 ubiquitination and stabilized LSD1 in A172 and T98G cells. MTT, EdU proliferation, flow cytometry and Transwell assays indicated that LSD1 played a critical role in the proliferation and invasion of glioblastoma (GBM) cells. We defined the mechanism of USP7 in GBM, through counterbalanced LSD1 ubiquitylation. USP7 caused G0/G1 arrest, promoted tumorigenesis and invasion of A172 and T98G cells. We also uncovered the suppression of the p53 signaling pathway that mediated the activity of USP7 and LSD1. Furthermore, USP7 and LSD1 expression levels were higher in the 150 glioma patients than these levels in normal brain tissues and were correlated with glioma progression. LSD1 was increased concurrently with USP7 during glioblastoma progression and both were predictors for worsened prognosis. Collectively, our study suggested that USP7-LSD1 affects GBM cell proliferation and invasion and may be valuable as novel therapeutic targets and prognostic tools for GBM.
authors.affiliation: Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yi
authors.affiliation: Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Qingfu
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000328:Adult; D000368:Aged; D063646:Carcinogenesis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D056466:Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025801:Ubiquitin / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis* / Q000235:genetics; D000076084:Ubiquitin-Specific Peptidase 7
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D056466:Histone Demethylases; C495195:KDM1A protein, human; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7