USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance

Lee, Jin Ku; Chang, Nakho; Yoon, Yong‐Ho; Yang, Heekyoung; Cho, Heejin; Kim, Eun‐Hee; Shin, Yongjae; Kang, Wonyoung; Oh, Young Taek; Mun, Gyeong In; Joo, Kyeung Min; Nam, Do Hyun; Lee, Jeongwu

doi:10.1093/neuonc/nov091

Cited by 84 publications

(63 citation statements)

References 41 publications

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“…Inhibition of ІRE1 signaling enzyme function in U87 glioma cells increased effect of glutamine deprivation on the expression of USP1 gene and introduced sensitivity of USP4 and USP14 genes to this condition. A decreased level of USP1, USP4, and USP14 mRNA expression upon glutamine deprivation agrees well with functional role of these enzymes and suppression of glioma cell proliferation, because there is data that USP1 targeting impedes GBM growth and that USP4 and USP14 regulate cellular proliferation and apoptosis [16,18,23].…”

Section: Resultssupporting

confidence: 68%

“…USP1 and USP7 are responsible for deubiquitination of mono-ubiquitinated PCNA (proliferating cell nuclear antigen), which activates error-prone DNA polymerases and controls an oxidative-stress-induced mutagenesis in human cells [13]. Decreased levels of USP1 in cancer cells have been implicated in lung and glioblastoma tumors growth and progression [14,16]. There is data that serine phosphorylation is critical for the activity of USP1 and its interaction with WD40-repeat protein UAF1; while two nuclear localization signals in USP1 media te nuclear import of the USP1/UAF1 complex [17].…”

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confidence: 99%

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Expression of ubiquitin specific peptidase and ATG7 genes in U87 glioma cells upon glutamine deprivation

Halkin¹,

Minchenko²,

Riabovol³

et al. 2017

Ukr.Biochem.J

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We have studied the effect of glutamine deprivation on the expression of genes encoding for ubiquitin specific peptidases (usP) [4][5][6]. A better knowledge of tumor respon ses to glutamine deprivation condition is required to elaborate new therapeutical strategies of cell sensibilization, based on the blockade of survival mechanisms.Ubiquitin is a highly conserved protein involved in regulation of intracellular protein breakdown, cell cycle regulation, chromatin remodeling, and stress response. It is released from degraded proteins by disassembly of the polyubiquitin chains, which is mediated by ubiquitin-specific proteases, members of the ubiquitin-specific processing family of proteases for deubiquitination of proteins [7][8][9]. E3 ubiquitin ligases and deubiquitylases play an important role in cancer [7,10,11]. Our previous results demonstrated possible interaction/cross-talk between unfolding protein response signaling and ubiquitin system during adjustment to episodes of hypoxia during tumor development [12]. Ubiquitin specific peptidases (USPs) and ubiquitin activating enzyme E1-like protein/autophagy related 7 (GSA7/ ATG7) are involved in cancer cells survival and progression [13][14][15]. USP1 and USP7 are responsible for deubiquitination of mono-ubiquitinated PCNA (proliferating cell nuclear antigen), which activates error-prone DNA polymerases and controls an oxidative-stress-induced mutagenesis in human cells [13]. Decreased levels of USP1 in cancer cells have been implicated in lung and glioblastoma tumors growth and progression [14,16]. There is data that serine phosphorylation is critical for the activity of USP1 and its interaction with WD40-repeat protein UAF1; while two nuclear localization signals

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Section: Resultssupporting

confidence: 68%

mentioning

confidence: 99%

Expression of ubiquitin specific peptidase and ATG7 genes in U87 glioma cells upon glutamine deprivation

Halkin¹,

Minchenko²,

Riabovol³

et al. 2017

Ukr.Biochem.J

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“…These findings show that PDGF signaling can upregulate Usp1 expression. Inhibition of USP1 has been previously shown to decrease proliferation of leukemia cells and spheroid formation of human glioblastoma cells (22,27). To examine whether Usp1 affects the survival of PDGF-GSCs, we infected these cells with lentiviruses encoding Usp1-targeting shRNAs (short hairpin RNAs) or a nontarget control (ShControl) and performed Annexin V/PI staining.…”

Section: Pdgf Signaling Regulates Usp1 Expression To Promote Survivalmentioning

confidence: 99%

“…Deubiquitinases (DUB), which include over 100 genes classified into five subgroups, catalyze the removal of ubiquitin molecules that are covalently bound to a substrate, thus diminishing its proteasomal degradation (17). Recent work has identified a role for USP1, a member of the ubiquitin-specific peptidase (USP) group of DUBs, in the regulation of tumor pathogenesis (19)(20)(21) including glioblastoma (22). Inhibition of USP1 by multiple strategies has been suggested as a potential strategy to enhance the therapeutic efficacy of chemotherapy and radiation in treating cancer (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

“…Recent work has identified a role for USP1, a member of the ubiquitin-specific peptidase (USP) group of DUBs, in the regulation of tumor pathogenesis (19)(20)(21) including glioblastoma (22). Inhibition of USP1 by multiple strategies has been suggested as a potential strategy to enhance the therapeutic efficacy of chemotherapy and radiation in treating cancer (22)(23)(24). USP1, upon forming a molecular complex with UAF1 (WDR48), deubiquitinates substrates including PCNA, FANCI, FANCD2, and the short-lived Inhibitor of DNA Binding (ID) proteins ID1, ID2, and ID3 that each have a half-life of about 10 minutes (19,20,(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

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PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells

et al. 2016

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Glioblastoma is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of glioblastoma has identified distinct molecular subtypes of glioblastoma. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in the proneural subtype of glioblastoma and can drive gliomagenesis. However, little is known about the downstream effectors of PDGF signaling in glioblastoma. Using a mouse model of proneural glioma and comparative transcriptomics, we determined that PDGF signaling upregulated ubiquitin-specific peptidase 1 (Usp1) to promote the survival of murine proneural glioma cells. Mechanistically, we found that PDGF signaling regulated the expression of the E2F transcription factors, which directly bound to and activated Usp1. Furthermore, PDGF-mediated expression of USP1 led to the stabilization of Inhibitor of DNA-binding 2 (ID2), which we found to be required for glioma cell survival. Genetic ablation of Id2 delayed tumor-induced mortality, and pharmacologic inhibition of USP1, resulting in decreased ID2 levels, also delayed tumorigenesis in mice. Notably, decreased USP1 expression was associated with prolonged survival in patients with proneural glioblastoma, but not with other subtypes of glioblastoma. Collectively, our findings describe a signaling cascade downstream of PDGF that sustains proneural glioblastoma cells and suggest that inhibition of the PDGF-E2F-USP1-ID2 axis could serve as a therapeutic strategy for proneural glioblastoma featuring increased PDGF signaling.

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Mutation of aspartic acid 199 in USP1 disrupts its deubiquitinating activity and impairs DNA repair

Jang

Kim

2021

FEBS Letters

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The deubiquitinating enzyme USP1 contains highly conserved motifs forming its catalytic center. Recently, the COSMIC mutation database identified a mutation in USP1 at Asp‐199 in endometrial cancer. Here, we investigated the role of Asp‐199 for USP1 function. The mutation of aspartic acid to alanine (D199A) resulted in failure of USP1 to undergo autocleavage and form a complex with ubiquitin, indicating D199A Usp1 is catalytically inactive. The D199A mutation did not affect the interaction with Uaf1. Moreover, D199A Usp1 had defects in deubiquitination of FANCD2 and PCNA and displayed reduced FANCD2 foci formation and DNA repair efficiency. Furthermore, mutation of Asp‐199 to glutamic acid resulted in phenotypes similar to the D199A mutation. Collectively, our findings demonstrate the importance of Asp‐199 for USP1 activity and suggest the implications of USP1 downregulation in cancer.

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USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance

Abstract: USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.

Cited by 84 publications

References 41 publications

Expression of ubiquitin specific peptidase and ATG7 genes in U87 glioma cells upon glutamine deprivation

Expression of ubiquitin specific peptidase and ATG7 genes in U87 glioma cells upon glutamine deprivation

PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells

Mutation of aspartic acid 199 in USP1 disrupts its deubiquitinating activity and impairs DNA repair

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