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Ajuba inhibits hepatocellular carcinoma cell growth via targeting of β-catenin and YAP signaling and is regulated by E3 ligase Hakai through neddylation

Overview of attention for article published in Journal of Experimental & Clinical Cancer Research, July 2018
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Title
Ajuba inhibits hepatocellular carcinoma cell growth via targeting of β-catenin and YAP signaling and is regulated by E3 ligase Hakai through neddylation
Published in
Journal of Experimental & Clinical Cancer Research, July 2018
DOI 10.1186/s13046-018-0806-3
Pubmed ID
Authors

Min Liu, Ke Jiang, Guibin Lin, Peng Liu, Yumei Yan, Tian Ye, Gang Yao, Martin P. Barr, Dapeng Liang, Yang Wang, Peng Gong, Songshu Meng, Haozhe Piao

Abstract

Aberrant activation of β-catenin and Yes-associated protein (YAP) signaling pathways has been associated with hepatocellular carcinoma (HCC) progression. The LIM domain protein Ajuba regulates β-catenin and YAP signaling and is implicated in tumorigenesis. However, roles and mechanism of Ajuba expression in HCC cells remain unclear. The E3 ligase Hakai has been shown to interact with other Ajuba family members and whether Hakai interacts and regulates Ajuba is unknown. HCC cell lines stably depleted of Ajuba or Hakai were established using lentiviruses expressing shRNAs against Ajuba or Hakai. The effects of Ajuba on HCC cells were determined by a number of cell-based analyses including anchorage-independent growth, three dimension cultures and trans-well invasion assay. In vivo tumor growth was determined in a xenograft model and Ajuba expression in tumor sections was examined by immunohistochemistry. Co-immunoprecipitation, confocal microscopy and immunoblot assay were used to examine the expression and interaction between Ajuba and Hakai. Depletion of Ajuba in HCC cells significantly enhanced anchorage-independent growth, invasion, the formation of spheroids and tumor growth in a xenograft model, suggesting a tumor suppressor function for Ajuba in HCC. Mechanistically, Ajuba depletion triggered E-cadherin loss and β-catenin translocation with increased Cyclin D1 levels. In addition, depletion of Ajuba upregulated the levels of YAP and its target gene CYR61. Furthermore, siRNA-mediated knockdown of either β-catenin or YAP attenuated the pro-tumor effects by Ajuba depletion on HCC cells. Notably, Ajuba stability in HCC cells was regulated by Hakai, an E3 ligase for E-cadherin. Hakai interacted with Ajuba via its HYB domain and induced Ajuba neddylation, which was antagonized by the neddylation inhibitor, MLN4924, but not MG132. We further show that overexpression of Hakai in HCC cells markedly increased anchorage-independent growth, spheroid-formation ability and tumor growth in xenografts whereas Hakai depletion resulted in these opposite effects, indicating an oncogenic role for Hakai in HCC. Hakai also induced β-catenin translocation with increased levels of Cyclin D1. Our data suggest a role for Ajuba and Hakai in HCC, and uncover the mechanism underlying the regulation of Ajuba stability.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 26 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 26 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 7 27%
Student > Bachelor 5 19%
Student > Doctoral Student 3 12%
Student > Master 3 12%
Other 1 4%
Other 4 15%
Unknown 3 12%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 11 42%
Medicine and Dentistry 5 19%
Agricultural and Biological Sciences 2 8%
Unspecified 1 4%
Pharmacology, Toxicology and Pharmaceutical Science 1 4%
Other 2 8%
Unknown 4 15%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 26 July 2018.
All research outputs
#11,789,301
of 13,285,014 outputs
Outputs from Journal of Experimental & Clinical Cancer Research
#675
of 910 outputs
Outputs of similar age
#232,342
of 268,304 outputs
Outputs of similar age from Journal of Experimental & Clinical Cancer Research
#1
of 1 outputs
Altmetric has tracked 13,285,014 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 910 research outputs from this source. They receive a mean Attention Score of 2.6. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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