USP2a Supports Metastasis by Tuning TGF-β Signaling

Zhao, Yin; Wang, Xiaomeng; Wang, Qingqing; Deng, Yu; Li, Kang; Zhang, Man; Zhang, Qiang; Zhou, Jin; Wang, Hongyan; Bai, Peng; Ren, Yujie; Zhang, Ni; Li, Weina; Cheng, Yongbo; Xiao, Wuhan; Du, Hai-Ning; Cheng, Xiaoxing; Yin, Lei; Fu, Xiangning; Lin, Dandan; Zhou, Qianghui; Zhong, Bo

doi:10.1016/j.celrep.2018.02.007

Cited by 57 publications

(49 citation statements)

References 39 publications

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“…The experiments were performed as previously described. 44,45,56,58,59 In brief, cells were lysed in Nonidet P-40 lysis buffer containing 150 mM NaCl, 1 mM EDTA, 1% Nonidet P-40, and 1% protease and phosphatase inhibitor cocktail (Biotool). Cell lysates were subjected to SDS-PAGE and immunoblot analysis was performed with the appropriate antibodies.…”

Section: Co-immunoprecipitation and Immunoblot Analysismentioning

confidence: 99%

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

Liuyu

et al. 2018

Cell Res

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The activity and stability of the adapter protein MAVS (also known as VISA, Cardif and IPS-1), which critically mediates cellular antiviral responses, are extensively regulated by ubiquitination. However, the process whereby MAVS is deubiquitinated is unclear.Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) targets MAVS for deubiquitination. Viral infection leads to the IRF3/7-dependent upregulation of OTUD4 which interacts with MAVS to remove K48-linked polyubiquitin chains, thereby maintaining MAVS stability and promoting innate antiviral signaling. Knockout or knockdown of OTUD4 impairs RNA virus-triggered activation of IRF3 and NF-κB, expression of their downstream target genes, and potentiates VSV replication in vitro and in vivo. Consistently, Cre-ER Otud4 fl/fl or Lyz2-Cre Otud4 fl/fl mice produce decreased levels of type I interferons and proinflammatory cytokines and exhibit increased sensitivity to VSV infection compared to their control littermates. In addition, reconstitution of MAVS into OTUD4-deficient cells restores virus-induced expression of downstream genes and cellular antiviral responses. Together, our findings uncover an essential role of OTUD4 in virus-triggered signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.

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Section: Co-immunoprecipitation and Immunoblot Analysismentioning

confidence: 99%

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

Liuyu

et al. 2018

Cell Res

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“…The c‐Myc also can be stabilized by USP2a, USP9X, and USP22 whereas the FASN and Aurora‐A can be stabilized by USP2a . The USP2a also can activate EMT through TGF‐β signalling through R‐SMADs‐SMAD4 complex…”

Section: Targeting the Signalling Pathway For Crpcmentioning

confidence: 68%

“…After that, the phosphorylated R‐SMADs split from the receptors and make a complex by binding with SMAD4. Then, the phosphorylated R‐SMADs‐SMAD4 complex translocated into the nucleus and upregulated EMT gene expression (Figure ) . The EMT can further bind with pAkt and increases the PCa progression and metastasis (Figure ) .…”

Section: Targeting the Signalling Pathway For Crpcmentioning

confidence: 99%

“…Then, the phosphorylated R-SMADs-SMAD4 complex translocated into the nucleus and upregulated EMT gene expression ( Figure 6). 97 The EMT can further bind with pAkt and increases the PCa progression and metastasis ( Figure 6). 25,27,60 In addition, the EMT transition can also be upregulated in PCa by growth factormediated PI3K activation.…”

Section: Targeting the Signalling Pathway For Crpcmentioning

confidence: 99%

“…60,[93][94][95] The c-Myc also can be stabilized by USP2a, USP9X, and USP22 whereas the FASN and Aurora-A can be stabilized by USP2a. 23,96 The USP2a also can activate EMT through TGF-β signalling through R-SMADs-SMAD4 complex 97 which is a strategy to inhibit this pathway by blocking it. 89,105 But it will be more effective if it is possible to find any DUBs which can regulate PI3K/pAkt pathway.…”

Section: Figurementioning

confidence: 99%

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Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics

Islam

Zhou

Chen

et al. 2019

Cell Biochemistry & Function

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Prostate cancer (PCa) is the most common cancer diagnosed and the second most common cause of cancer‐related death in men worldwide. The current androgen deprivation therapy for PCa cannot fully cure this disease. Moreover, androgen receptor gene amplification and mutation are associated with PCa to develop castration‐resistant prostate cancer (CRPC). This review focuses on the deubiquitinases (DUBs) involved in PCa development and progression. For PCa development and progression, several cellular pathways are regulated by specific DUBs which are also highlighted in here. The ubiquitin‐specific proteases (USPs), a family member of DUBs mostly involved in the regulation of cellular pathways for PCa development, and the ubiquitin C‐terminal hydrolases (UCHs), another family member of DUBs, are responsible for PCa metastasis. Small molecular inhibitors against DUBs can inhibit or reduce the level of specific DUBs through the regulation of cellular pathway to treat this disease. Some small molecular inhibitors are already identified against some of the DUBs, but very few of them are clinically proved in PCa. So, to find out other DUBs involving in the regulation of PCa‐related pathways and to develop more effective small molecule inhibitors with greater potency would be a great idea to target PCa cells for future therapeutics and drug development with or without the combination of other anticancer drugs. Significance of the study This review is targeting DUB proteins which are responsible for PCa induction, proliferation, and metastasis by highlighting their signalling pathway so that the readers can get information about other mechanisms for PCa besides androgen receptor pathway and helps to find other oncogenic DUBs involving in these signalling pathways. This review also hopes to find other oncogenic DUBs involving in PCa‐related signalling pathways or to find the DUBs that can regulate multiple oncogenic signalling pathways which might be a good target for PCa therapeutics. In addition, there are some small molecule inhibitors that can inhibit the oncogenic DUBs and thus able to control the oncogenic pathways which would be a novel strategy to treat CRPC by using DUB inhibitor combined with or without other anticancer drugs.

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IL‐36γ and IL‐36Ra Reciprocally Regulate NSCLC Progression by Modulating GSH Homeostasis and Oxidative Stress‐Induced Cell Death

et al. 2021

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The balance between antioxidants and reactive oxygen species (ROS) critically regulates tumor initiation and progression. However, whether and how the tumor-favoring redox status is controlled by cytokine networks remain poorly defined. Here, it is shown that IL-36 and IL-36Ra reciprocally regulate the progression of non-small cell lung cancer (NSCLC) by modulating glutathione metabolism and ROS resolution. Knockout, inhibition, or neutralization of IL-36 significantly inhibits NSCLC progression and prolongs survival of the Kras LSL-G12D/+ Tp53 fl/fl and Kras LSL-G12D/+ Lkb1 fl/fl mice after tumor induction, whereas knockout of IL-36Ra exacerbates tumorigenesis in these NSCLC mouse models and accelerates death of mice. Mechanistically, IL-36 directly upregulates an array of genes involved in glutathione homeostasis to reduce ROS and prevent oxidative stress-induced cell death, which is mitigated by IL-36Ra or IL-36 neutralizing antibody. Consistently, IL-36 staining is positively and negatively correlated with glutathione biosynthesis and ROS in human NSCLC tumor biopsies, respectively. These findings highlight essential roles of cytokine networks in redox for tumorigenesis and provide potential therapeutic strategy for NSCLC.

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USP2a Supports Metastasis by Tuning TGF-β Signaling

Cited by 57 publications

References 39 publications

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics

IL‐36γ and IL‐36Ra Reciprocally Regulate NSCLC Progression by Modulating GSH Homeostasis and Oxidative Stress‐Induced Cell Death

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