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USP10 deubiquitinates RUNX1 and promotes proneural-to-mesenchymal transition in glioblastoma.

ABSTRACT: The mesenchymal (MES) subtype of glioblastoma (GBM) is a highly aggressive, malignant and proliferative cancer that is resistant to chemotherapy. Runt-related transcription factor 1 (RUNX1) was shown to support MES GBM, however, its underlying mechanisms are unclear. Here, we identified USP10 as a deubiquitinating enzyme that regulates RUNX1 stabilization and is mainly expressed in MES GBM. Overexpression of USP10 upregulated RUNX1 and induced proneural-to-mesenchymal transition (PMT), thus maintaining MES properties in GBM. Conversely, USP10 knockdown inhibited RUNX1 and resulted in the loss of MES properties. USP10 was shown to interact with RUNX1, with RUNX1 being stabilized upon deubiquitylation. Moreover, we found that USP10 inhibitor Spautin-1 induced RUNX1 degradation and inhibited MES properties in vitro and in vivo. Furthermore, USP10 was strongly correlated with RUNX1 expression in samples of different subtypes of human GBM and had prognostic value for GBM patients. We identified USP10 as a key deubiquitinase for RUNX1 protein stabilization. USP10 maintains MES properties of GBM, and promotes PMT of GBM cells. Our study indicates that the USP10/RUNX1 axis may be a potential target for novel GBM treatments.

SUBMITTER: Qiu W

PROVIDER: S-EPMC10033651 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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USP10 deubiquitinates RUNX1 and promotes proneural-to-mesenchymal transition in glioblastoma.

Qiu Wenjin W Xiao Zumu Z Yang Yushi Y Jiang Lishi L Song Shibin S Qi Xiaolan X Chen Yimin Y Yang Hua H Liu Jian J Chu Liangzhao L

Cell death & disease 20230322 3

The mesenchymal (MES) subtype of glioblastoma (GBM) is a highly aggressive, malignant and proliferative cancer that is resistant to chemotherapy. Runt-related transcription factor 1 (RUNX1) was shown to support MES GBM, however, its underlying mechanisms are unclear. Here, we identified USP10 as a deubiquitinating enzyme that regulates RUNX1 stabilization and is mainly expressed in MES GBM. Overexpression of USP10 upregulated RUNX1 and induced proneural-to-mesenchymal transition (PMT), thus main ...[more]

PMID: 36949071

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Project description:BackgroundResistance to temozolomide (TMZ) is a major obstacle to preventing glioblastoma (GBM) recurrence after surgery. Although long noncoding RNAs (lncRNAs) play a variety of roles in GBM, the lncRNAs that regulate TMZ resistance have not yet been clearly elucidated. This study aims to identify lncRNAs that may affect TMZ treatment sensitivity and to explore novel therapeutic strategies to overcome TMZ resistance in GBM.MethodsLncRNAs associated with TMZ resistance were identified using the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets. Quantitative real-time PCR (qRT-PCR) was used to determine the expression of PDIA3P1 in TMZ-resistant and TMZ-sensitive GBM cell lines. Both gain-of-function and loss-of-function studies were used to assess the effects of PDIA3P1 on TMZ resistance using in vitro and in vivo assays. Glioma stem cells (GSCs) were used to determine the effect of PDIA3P1 on the GBM subtype. The hypothesis that PDIA3P1 promotes proneural-to-mesenchymal transition (PMT) was established using bioinformatics analysis and functional experiments. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to examine the interaction between PDIA3P1 and C/EBPβ. The posttranslational modification mechanism of C/EBPβ was verified using ubiquitination and coimmunoprecipitation (co-IP) experiments. CompuSyn was leveraged to calculate the combination index (CI), and the antitumor effect of TMZ combined with nefllamapimod (NEF) was validated both in vitro and in vivo.ResultsWe identified a lncRNA, PDIA3P1, which was upregulated in TMZ-resistant GBM cell lines. Overexpression of PDIA3P1 promoted the acquisition of TMZ resistance, whereas knockdown of PDIA3P1 restored TMZ sensitivity. PDIA3P1 was upregulated in MES-GBM, promoted PMT progression in GSCs, and caused GBMs to be more resistant to TMZ treatment. Mechanistically, PDIA3P1 disrupted the C/EBPβ-MDM2 complex and stabilized the C/EBPβ protein by preventing MDM2-mediated ubiquitination. Expression of PDIA3P1 was upregulated in a time- and concentration-dependent manner in response to TMZ treatment, and TMZ-induced upregulation of PDIA3P1 was mediated by the p38α-MAPK signaling pathway. NEF is a small molecule drug that specifically targets p38α with excellent blood-brain barrier (BBB) permeability. NEF blocked TMZ-responsive PDIA3P1 upregulation and produced synergistic effects when combined with TMZ at specific concentrations. The combination of TMZ and NEF exhibited excellent synergistic antitumor effects both in vitro and in vivo.ConclusionPDIA3P1 promotes PMT by stabilizing C/EBPβ, reducing the sensitivity of GBM cells to TMZ treatment. NEF inhibits TMZ-responsive PDIA3P1 upregulation, and NEF combined with TMZ provides better antitumor effects.

Dataset Information

USP10 deubiquitinates RUNX1 and promotes proneural-to-mesenchymal transition in glioblastoma.

Publications

USP10 deubiquitinates RUNX1 and promotes proneural-to-mesenchymal transition in glioblastoma.

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