An integrated bioinformatics platform for investigating the human E3 ubiquitin ligase-substrate interaction network

Li, Yang; Xie, Ping; Liang, Lu; Wang, Jian; Diao, Lihong; Liu, Zhongyang; Guo, Feifei; He, Yangzhige; Liu, Yuan; Huang, Qin; Liang, Han; Liu, Dong; He, Fuchu

doi:10.1038/s41467-017-00299-9

Cited by 177 publications

(157 citation statements)

References 57 publications

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“…Based on the interactome landscape from BioGRID, STIL may interact with ubiquitin‐specific protease 7 (USP7), which represses the auto‐ubiquitination of checkpoint with forkhead and ring finger domains (CHFR)‐E3 ubiquitin ligase . Intriguingly, SP3 was predicted as a high‐score substrate of CHFR by the UbiBrowser . Taken together, STIL regulates oncogenic IGF‐1/PI3K/AKT pathway in GC, which may attribute to its interaction with the USP7/CHFR/SP3 signaling axis.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of STIL suppresses the progression of gastric cancer by down‐regulating the IGF‐1/PI3K/AKT pathway

Wang

Zhang

Dou

et al. 2019

J Cellular Molecular Medi

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SCL/TAL1 interrupting locus (STIL) regulates the mitotic centrosome to promote the centriolar replication and cell cycling, and is associated with malignancies. However, the role and mechanism of STIL in gastric cancer (GC) remain elusive. STIL expression in GC tissue microarray was detected by immunohistochemistry (IHC). GC cells were transduced with control lentivirus or lentivirus for expression STIL‐specific shRNA and the effect of STIL silencing on the malignant behaviors of GC cells was measured in vitro and in vivo. The potential mechanisms underlying the action of STIL were analyzed by transcriptome microarray and bioinformatics. STIL expression was up‐regulated in GC tissues both in our cohort and the data from the cancer genome atlas, and positively associated with T stage and poor overall survival of GC patients. Knockdown of STIL significantly inhibited the proliferation and clonogenicity of human GC cells and attenuated the growth of implanted GC in vivo. Furthermore, STIL silencing induced cell cycle arrest in G2/M phase and apoptosis of GC cells. Transcriptome analysis indicated that STIL silencing modulated many gene expression, particularly for down‐regulating the IGF‐1/PI3K/AKT pathway. In addition, treatment with SC79, an AKT activator, significantly mitigated the effect of STIL‐silencing in GC cells. In conclusion, STIL promotes gastric carcinogenesis and progression by enhancing the IGF‐1/PI3K/AKT signaling, and STIL may be a novel target for intervention of GC.

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Section: Discussionmentioning

confidence: 99%

Knockdown of STIL suppresses the progression of gastric cancer by down‐regulating the IGF‐1/PI3K/AKT pathway

Wang

Zhang

Dou

et al. 2019

J Cellular Molecular Medi

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“…Single gene GSEA based on the TCGA database was used to explore the pathway differences between samples with high and low expressions of VIM and ABCC1 [40]. The E3substrate interaction network (http://ubibrowser.ncpsb.org/) was used to predict the E3s of VIM and ABCC1 [41]. Equal amounts of protein samples were separated with 10% sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) and transferred onto polyvinylidene difluoride (PVDF) membranes.…”

Section: Lscc Transcriptomics Data and Statistical Analysismentioning

confidence: 99%

Label-free quantitative identification of abnormally ubiquitinated proteins as useful biomarkers for human lung squamous cell carcinomas

Chen²,

Zhuang

et al. 2020

EPMA Journal

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Background Ubiquitination is an important molecular event in lung squamous cell carcinoma (LSCC), which currently is mainly studied in nonsmall cell lung carcinoma cell models but lacking of ubiquitination studies on LSCC tissues. Here, we presented the ubiquitinated protein profiles of LSCC tissues to explore ubiquitination-involved molecular network alterations and identify abnormally ubiquitinated proteins as useful biomarkers for predictive, preventive, and personalized medicine (PPPM) in LSCC. Methods Anti-ubiquitin antibody-based enrichment coupled with LC-MS/MS was used to identify differentially ubiquitinated proteins (DUPs) between LSCC and control tissues, followed by integrative omics analyses to identify abnormally ubiquitinated protein biomarkers for LSCC. Results Totally, 400 DUPs with 654 ubiquitination sites were identified,, and motifs AX (1/2/3)-K* were prone to be ubiquitinated in LSCC tissues. Those DUPs were involved in multiple molecular network systems, including the ubiquitinproteasome system (UPS), cell metabolism, cell adhesion, and signal transduction. Totally, 44 hub molecules were revealed by protein-protein interaction network analysis, followed by survival analysis in TCGA database (494 LSCC patients and 20,530 genes) to obtain 18 prognosis-related mRNAs, of which the highly expressed mRNAs VIM and IGF1R were correlated with poorer prognosis, while the highly expressed mRNA ABCC1 was correlated with better prognosis. VIM-encoded protein vimentin and ABCC1-encoded protein MRP1 were increased in LSCC, which were all associated with poor prognosis. Proteasome-inhibited experiments demonstrated that vimentin and MRP1 were degraded through UPS. Quantitative ubiquitinomics found ubiquitination level was decreased in vimentin and increased in MRP1 in LSCC. These findings showed that the increased vimentin in LSCC might be derived from its decreased ubiquitination level and that the increased MRP1 in LSCC might be derived from its protein synthesis > degradation. GSEA and co-expression gene analyses revealed that VIM and Electronic supplementary material The online version of this article (

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“…However, the mechanism underlying its downregulation in tumor progression has been unclear. We used UbiBrowser software (http://ubibrowser.ncpsb.org/ubibrowser/home/index) (42) to predict the E3 ubiquitin ligase of SIRT2 and found that SYVN1 (HRD1) was a candidate (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation

Liu

Zeng

et al. 2020

Molecular and Cellular Biology

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The NAD-dependent histone deacetylase sirtuin 2 (SIRT2) plays critical roles in mitosis and cell cycle progression and recently was shown to suppress tumor growth and to be downregulated in several types of cancers. However, the underlying mechanism of SIRT2 downregulation remains unknown. In this study, using bioinformatics, gene expression profiling, protein overexpression approaches, and cell migration assays, we showed that E3 ubiquitin ligase 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase degradation 1 (HRD1) interacts with SIRT2 and promotes its ubiquitination and degradation. Furthermore, we found that HRD1 deficiency induces SIRT2 upregulation and inhibits the growth and tumor formation of lung cancer cells both in vitro and in vivo. Of note, we observed that SIRT2 expression is downregulated in human lung cancer and also negatively correlates with HRD1 expression in these cancers. Additionally, we found that patients with lung adenocarcinoma having lower HRD1 or higher SIRT2 expression levels tend to survive longer. On the basis of these results, we propose a mechanism of lung tumorigenesis that involves HRD1-mediated downregulation of SIRT2 and suggest that interventions targeting HRD1 activity could be a potential therapeutic strategy to treat patients with lung cancer.

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An integrated bioinformatics platform for investigating the human E3 ubiquitin ligase-substrate interaction network

Cited by 177 publications

References 57 publications

Knockdown of STIL suppresses the progression of gastric cancer by down‐regulating the IGF‐1/PI3K/AKT pathway

Knockdown of STIL suppresses the progression of gastric cancer by down‐regulating the IGF‐1/PI3K/AKT pathway

Label-free quantitative identification of abnormally ubiquitinated proteins as useful biomarkers for human lung squamous cell carcinomas

E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation

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