Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein

Yuan, Tao; Chen, Zibo; Yan, Fang-Jie; Qian, Meijia; Luo, Hong; Song, Yang; Cao, Ji; Ying, Meidan; Dai, Xiaohu; Gai, Renhua; Yang, Bo; He, Qiaojun; Zhu, Hong

doi:10.1002/1878-0261.12596

Cited by 51 publications

(52 citation statements)

References 40 publications

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“…The HECT E3 ligase Smurf1 carries out very similar functions to Smurf2 by also binding to Smad7, however it does not coprecipitate with USP15 indicating a contextually different, USP15/Smurf2-independent role (239,290). Downstream of receptor complex activation, the DUB USP10 drives TGF-b signaling by stabilizing Smad4 which has been linked to increased metastatic potential in hepatocellular carcinoma (291). Another HECT E3 ligase, NEDD4L, recognizes the phosphorylated PPXY motif of Smad2/3 via its WW domain, resulting in polyubiquitin-mediated turnover and reduced TGF-b signaling output (292).…”

Section: Tgf-b Signalingmentioning

confidence: 99%

Targeting the Ubiquitin System in Glioblastoma

et al. 2020

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Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.

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Section: Tgf-b Signalingmentioning

confidence: 99%

Targeting the Ubiquitin System in Glioblastoma

et al. 2020

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“…3). We also compared the effect on migration of USP19 silencing with USP10 silencing, one of the already published candidate genes obtained from our screen [38][39][40]. Our results indicate that knock down of both genes impair migration to a similar extent (Supp.…”

Section: Validation Of Usp19 As a Regulator Of Cell Migrationmentioning

confidence: 70%

USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

Rossi

Steinberg

Calvo-Roitberg

et al. 2020

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ABSTRACTTumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The Ubiquitin-Proteasome System (UPS) plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against UPS-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly aggressive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

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“…4 ). We also compared the effect on migration of USP19 silencing with USP10 silencing, one of the already published candidate genes obtained from our screen 39 – 41 . Our results indicate that knock down of both genes impair migration to a similar extent (Supp.…”

Section: Resultsmentioning

confidence: 99%

USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

et al. 2021

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Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

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Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein

Cited by 51 publications

References 40 publications

Targeting the Ubiquitin System in Glioblastoma

Targeting the Ubiquitin System in Glioblastoma

USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

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