OTUB1 suppresses Hippo signaling via modulating YAP protein in gastric cancer

Yan, CH; Yang, Huijie; Su, Peng; Li, Xin; Li, Zhongbo; Wang, Dehai; Zang, Yifeng; Wang, Tianshi; Liu, Ziping; Bao, Zhuocong; Dong, Shuxiao; Zhuang, Ting; Zhu, Jian; Ding, Youming

doi:10.1038/s41388-022-02507-3

Cited by 31 publications

(21 citation statements)

References 33 publications

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“…According to Jianing Tang et al, USP26 and TAZ form a complex that decreases TAZ ubiquitination levels and regulates anaplastic thyroid cancer progression [32]. Furthermore, our previous studies verified that OTUB1 and DUB1 promote gastric cancer cell progression and invasion by positively regulating Hippo signaling [22,33]. OTUB1 was found to interact with YAP and subsequently inhibit YAP degradation.…”

Section: Discussionmentioning

confidence: 57%

USP1 modulates hepatocellular carcinoma progression via the Hippo/TAZ axis

Liu

Zang

et al. 2023

Cell Death Dis

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Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. The Hippo signaling pathway has emerged as a significant suppressive pathway for hepatocellular carcinogenesis. The core components of the Hippo pathway constitute a kinase cascade, which inhibits the functional activation of YAP/TAZ. Interestingly, the overactivation of YAP/TAZ is commonly observed in hepatocellular carcinoma, although the inhibitory kinase cascade of the Hippo pathway is still functional. Recent studies have indicated that the ubiquitin‒proteasome system also plays important roles in modulating Hippo signaling activity. Our DUB (deubiquitinase) siRNA screen showed that USP1 is a critical regulator of Hippo signaling activity. Analysis of TCGA data demonstrated that USP1 expression is elevated in HCC and associated with poor survival in HCC patients. RNA sequencing analysis revealed that USP1 depletion affects Hippo signaling activity in HCC cell lines. Mechanistic assays revealed that USP1 is required for Hippo/TAZ axis activity and HCC progression. USP1 interacted with the WW domain of TAZ, which subsequently enhanced TAZ stability by suppressing K11-linked polyubiquitination of TAZ. Our study identifies a novel mechanism linking USP1 and TAZ in regulating the Hippo pathway and one possible therapeutic target for HCC.

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Section: Discussionmentioning

confidence: 57%

USP1 modulates hepatocellular carcinoma progression via the Hippo/TAZ axis

Liu

Zang

et al. 2023

Cell Death Dis

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“…It is noteworthy that the significance of both OTUB1 and YAP has been underscored in lung, gastric, and breast cancers. 20,36,37 The Hippo signaling pathway serves as a crucial cellular signaling pathway that governs a wide range of biological processes. 38 In an active state of the Hippo pathway, the LATS1/2 kinase phosphorylates and inhibits YAP, leading to its sequestration in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that OTUB1‐YAP1 axis may play an important role in HNSCC progression. It is noteworthy that the significance of both OTUB1 and YAP has been underscored in lung, gastric, and breast cancers 20,36,37 …”

Section: Discussionmentioning

confidence: 99%

Involvement of the OTUB1‐YAP1 axis in driving malignant behaviors of head and neck squamous cell carcinoma

Jin,

Tsunematsu,

Horiguchi

et al. 2023

Cancer Medicine

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BackgroundComprehending the molecular mechanisms underlying head and neck squamous cell carcinoma (HNSCC) is vital for the development of effective treatment strategies. Deubiquitinating enzymes (DUBs), which regulate ubiquitin‐dependent pathways, are potential targets for cancer therapy because of their structural advantages. Here we aimed to identify a potential target for HNSCC treatment among DUBs.MethodsA screening process was conducted using RNA sequencing data and clinical information from HNSCC patients in the TCGA database. A panel of 88 DUBs was analyzed to identify those associated with poor prognosis. Subsequently, HNSCC cells were modified to overexpress specific DUBs, and their effects on cell proliferation and invasion were evaluated. In vivo experiments were performed to validate the findings.ResultsIn HNSCC patients, USP10, USP14, OTUB1, and STAMBP among the screened DUBs were associated with a poor prognosis. Among them, OTUB1 showed the most aggressive characteristics in both in vitro and in vivo experiments. Additionally, OTUB1 regulated the stability and nuclear localization of YAP1, a substrate involved in cell proliferation and invasion. Notably, OTUB1 expression exhibited a positive correlation with the HNSCC‐YAP score in HNSCC cells.ConclusionsThis study highlights the critical role of OTUB1 in HNSCC progression via modulating YAP1. Targeting the OTUB1‐YAP1 axis holds promise as a potential therapeutic strategy for HNSCC treatment.

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“…Ubiquitination plays a key role in several types of cancers by affecting posttranslational modifications [ 30 ]. The regulation of some protein ubiquitination by USP2 in different kinds of tumors has been reported [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

USP2 Inhibits Lung Cancer Pathogenesis by Reducing ARID2 Protein Degradation via Ubiquitination

Zhu

Chen

Guo

et al. 2022

BioMed Research International

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Background. Ubiquitination is an important regulator in physiological and pathological conditions. Ubiquitin-specific protease 2 (USP2), as a member of the USP family, exhibits oncogenic effects in multiple malignancies. However, the exact role of USP2 has not been well clarified in lung cancer pathogenesis and progression. Therefore, we aimed to further investigate the regulatory roles of USP2 in lung cancer in this study. Methods. Firstly, immunoprecipitation-Mass Spectrometry (IP-MS), Co-immunoprecipitation (Co-IP), combined with immunofluorescent colocalization method, was conducted for USP2 protein interaction analysis in lung cancer cell lines. qRT-PCR, Western blot, and immunohistochemistry assays explored the USP2 expression pattern and USP2/ARID2- (AT-rich interactive domain 2-) specific shRNAs and overexpression vectors. Co-IP assays were designed to validate USP2-ARID2 protein interaction. Further functional studies including CHX chase assay, transwell assay, and wound healing assay were subsequently applied to evaluate the impact of USP2 modulation on lung cancer cells. Results. USP2 suppression was characteristic in lung cancer cell line models and lung cancer samples. USP2 and ARID2 demonstrated protein-protein interaction and overlapping localization in cancer cell models. Functional experiments suggested USP2 inhibited lung cancer cell invasion and migration by reducing ARID2 protein degradation. Subsequent ubiquitination assays indicated ARID2 protein degradation via the ubiquitination was significantly reduced by USP2 interaction. Conclusions. Our study provided novel insight that USP2 might suppress lung cancer by reducing ARID2 protein degradation via ubiquitination.

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OTUB1 suppresses Hippo signaling via modulating YAP protein in gastric cancer

Cited by 31 publications

References 33 publications

USP1 modulates hepatocellular carcinoma progression via the Hippo/TAZ axis

USP1 modulates hepatocellular carcinoma progression via the Hippo/TAZ axis

Involvement of the OTUB1‐YAP1 axis in driving malignant behaviors of head and neck squamous cell carcinoma

USP2 Inhibits Lung Cancer Pathogenesis by Reducing ARID2 Protein Degradation via Ubiquitination

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