The oncogenic role of ubiquitin specific peptidase (USP8) and its signaling pathways targeting for cancer therapeutics

Islam, Towhidul; Chen, Fangzhi; Chen, Hanchun

doi:10.1016/j.abb.2021.108811

Cited by 39 publications

(40 citation statements)

References 67 publications

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“…Increasing studies have revealed that the elevated expression of human USP8 correlates with tumorigenesis, including proliferation and metastasis [ 34 ]. USP8 promotes the progression of breast cancer via deubiquitinating and stabilizing Connexin-43 (Cx43) and Notch1 intracellular domain (NICD) [ 24 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Usp8 promotes tumor cell migration through activating the JNK pathway

et al. 2022

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Tumor metastasis is the most cause of high mortality for cancer patients. Identification of novel factors that modulate tumor cell migration is of great significance for therapeutic strategies. Here, we find that the ubiquitin-specific protease 8 (Usp8) promotes tumor cell migration through activating the c-Jun N-terminal kinase (JNK) pathway. Genetic epistasis analyses uncover Usp8 acts upstream of Tak1 to control the JNK pathway. Consistently, biochemical results reveal that Usp8 binds Tak1 to remove ubiquitin modification from Tak1, leading to its stabilization. In addition, human USP8 also triggers tumor cell migration and activates the JNK pathway. Finally, we show that knockdown of USP8 in human breast cancer cells suppresses cell migration. Taken together, our findings demonstrate that a conserved Usp8-Tak1-JNK axis promotes tumor cell migration, and providing USP8 as a potential therapeutic target for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Usp8 promotes tumor cell migration through activating the JNK pathway

et al. 2022

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“…USP8, a deubiquitinase, counters NRDP1 autoubiquitination and thereby increases NRDP1 levels [32]. Inhibition of USP8 has been shown to decrease NRDP1 levels and decrease cell proliferation and drug resistance in several cancers including breast, lung, and cervical cancer [47]. For example, knockdown of USP8 in lung cancer cells inhibited the proliferation of lung cancer cells by regulating several cell cycle and apoptosis-related proteins [48].…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes

Steele

Sam

Evans

et al. 2021

Cancers

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To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation followed by western blot analysis revealed a strong association between AR and NRDP1 localization when AR expression and/or cellular localization was manipulated via treatment with R1881, AR-specific siRNA, or enzalutamide. Transfection of LNCaP with various NRDP1 and AR constructs followed by immunoprecipitation confirmed binding of NRDP1 to AR is possible and determined that binding requires the hinge region of AR. Co-transfection with NRDP1 constructs and HA-ubiquitin followed by subcellular fractionation confirmed that nuclear NRDP1 retains its ubiquitin ligase activity. We also show that increased nuclear NRDP1 is associated with PSA recurrence in CaP patients (n = 162, odds ratio; 1.238, p = 0.007) and that higher levels of nuclear NRDP1 are found in castration resistant cell lines (CWR22Rv1 and PC3) compared to androgen sensitive cell lines (LNCaP and MDA-PCa-3B). The combined data indicate that NRDP1 plays a role in mediating CaP progression and supports further investigation of both the mechanism by which nuclear transport occurs and the identification of specific nuclear targets.

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“…Ubiquitin-specific proteases (USPs) as a deubiquitinases, regulate multiple fundamental cellular processes including cell proliferation, cell cycle, and cancer progression by removing ubiquitin from the substrate proteins [ 1 , 2 ]. However, recent evidences have demonstrated that ubiquitin specific peptidase 8 (USP8) stabilizes oncogenes and proto-oncogenes, therefore promoting cancer progression and survival through the activation of multiple signaling pathways [ 1 , 3 , 4 ]. It is critically associated with the movement of the ubiquitin from oncogenes and proto-oncogenes, and thus protect the proteins from degradation [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, recent evidences have demonstrated that ubiquitin specific peptidase 8 (USP8) stabilizes oncogenes and proto-oncogenes, therefore promoting cancer progression and survival through the activation of multiple signaling pathways [ 1 , 3 , 4 ]. It is critically associated with the movement of the ubiquitin from oncogenes and proto-oncogenes, and thus protect the proteins from degradation [ 3 , 4 ]. Depending with the ubiquitination linkages, the ubiquitinated substrate proteins can either play part in the regulation of protein degradation pathway, like in the case of K48-linkage ubiquitination, or functional regulation of cellular signaling, like in the case of K63-linkage ubiquitination [5] , [6] , [7] .…”

Section: Introductionmentioning

confidence: 99%

USP8 regulates liver cancer progression via the inhibition of TRAF6-mediated signal for NF-κB activation and autophagy induction by TLR4

Kim

Choi

Kim

et al. 2022

Translational Oncology

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Highlights The cellular activity of USPs is functionally implicated in cancer progression. USP8 negatively regulates the TRAF6-mediated signals for NF-κB and autophagy. USP8 KO SK-HEP-1 cells reveal increases of cancer progression in vivo and in vitro . TCGA and transcriptome data support the functional role of USP8 in liver cancers.

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The oncogenic role of ubiquitin specific peptidase (USP8) and its signaling pathways targeting for cancer therapeutics

Cited by 39 publications

References 67 publications

Usp8 promotes tumor cell migration through activating the JNK pathway

Usp8 promotes tumor cell migration through activating the JNK pathway

Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes

USP8 regulates liver cancer progression via the inhibition of TRAF6-mediated signal for NF-κB activation and autophagy induction by TLR4

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