OTUD4 promotes the progression of glioblastoma by deubiquitinating CDK1 and activating MAPK signaling pathway

作者全名："Ci, Mingxin; Zhao, Gaichao; Li, Chongyang; Liu, Ruochen; Hu, Xiaosong; Pan, Jun; Shen, Yang; Zhang, Guanghui; Li, Yongsen; Zhang, Li; Liang, Ping; Cui, Hongjuan"

作者地址："[Ci, Mingxin; Zhao, Gaichao; Li, Chongyang; Liu, Ruochen; Hu, Xiaosong; Pan, Jun; Shen, Yang; Zhang, Guanghui; Li, Yongsen; Cui, Hongjuan] Southwest Univ, Med Res Inst, State Key Lab Resource Insects, Chongqing 400715, Peoples R China; [Ci, Mingxin; Zhao, Gaichao; Li, Chongyang; Liu, Ruochen; Hu, Xiaosong; Pan, Jun; Shen, Yang; Zhang, Guanghui; Li, Yongsen; Cui, Hongjuan] Jinfeng Lab, Chongqing 401329, Peoples R China; [Zhang, Li] HeBei Med Univ, Hosp 1, Dept Radiol & Nucl Med, Shijiazhuang 050000, Hebei, Peoples R China; [Liang, Ping] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Neurosurg, Childrens Hosp ,Minist Educ,Key Lab Child Dev & Di, Chongqing 400014, Peoples R China"

通信作者："Cui, HJ (通讯作者)，Southwest Univ, Med Res Inst, State Key Lab Resource Insects, Chongqing 400715, Peoples R China.; Cui, HJ (通讯作者)，Jinfeng Lab, Chongqing 401329, Peoples R China.; Zhang, L (通讯作者)，HeBei Med Univ, Hosp 1, Dept Radiol & Nucl Med, Shijiazhuang 050000, Hebei, Peoples R China.; Liang, P (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Neurosurg, Childrens Hosp ,Minist Educ,Key Lab Child Dev & Di, Chongqing 400014, Peoples R China."

来源：CELL DEATH & DISEASE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001179020200004

JCR分区：Q1

影响因子：8.1

年份：2024

卷号：15

期号：3

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Glioblastoma, IDH-Wild type (GBM, CNS WHO Grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor with high morbidity, high mortality, and poor patient prognosis. The global burden of GBM is increasing notably due to limited treatment options, drug delivery problems, and the lack of characteristic molecular targets. OTU deubiquitinase 4 (OTUD4) is a potential predictive factor for several cancers such as breast cancer, liver cancer, and lung cancer. However, its function in GBM remains unknown. In this study, we found that high expression of OTUD4 is positively associated with poor prognosis in GBM patients. Moreover, we provided in vitro and in vivo evidence that OTUD4 promotes the proliferation and invasion of GBM cells. Mechanism studies showed that, on the one hand, OTUD4 directly interacts with cyclin-dependent kinase 1 (CDK1) and stabilizes CDK1 by removing its K11, K29, and K33-linked polyubiquitination. On the other hand, OTUD4 binds to fibroblast growth factor receptor 1 (FGFR1) and reduces FGFR1's K6 and K27-linked polyubiquitination, thereby indirectly stabilizing CDK1, ultimately influencing the activation of the downstream MAPK signaling pathway. Collectively, our results revealed that OTUD4 promotes GBM progression via OTUD4-CDK1-MAPK axis, and may be a prospective therapeutic target for GBM treatment."

基金机构：Natural Science Foundation of Chongqing [cstc2022ycjh-bgzxm0145]; Southwest University [SWU-XDZD22006]; Chongqing postgraduate Research Innovation Project [CYS22257]

基金资助正文："This research was supported by the Natural Science Foundation of Chongqing (cstc2022ycjh-bgzxm0145), the pilot program of Southwest University (SWU-XDZD22006) and the Chongqing postgraduate Research Innovation Project (CYS22257). We thank all the participants for their contributions to the study."