DUB1 suppresses Hippo signaling by modulating TAZ protein expression in gastric cancer

Background The Hippo pathway functions as a tumor suppressor pathway in human cancers, while dysfunction of the Hippo pathway is frequently observed in malignancies. Although YAP/TAZ activity is tightly controlled by the phosphorylation cascade of the MST-LATS-YAP/TAZ axis, it is still unclear why t...

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Published in:Journal of experimental & clinical cancer research 2022-07, Vol.41 (1), p.1-219, Article 219
Main Authors: Wang, Dehai, Li, Zhongbo, Li, Xin, Yan, Cheng, Yang, Huijie, Zhuang, Ting, Wang, Xiao, Zang, Yifeng, Liu, Ziping, Wang, Tianshi, Jiang, Rixia, Su, Peng, Zhu, Jian, Ding, Yinlu
Format: Article
Language:English
Subjects:
Analysis
Cancer
Deubiquitination
Development and progression
DUB1
Gastric cancer
Health aspects
Homeostasis
Kinases
Medical prognosis
Phosphorylation
Plasmids
Protein expression
Proteins
Stabilize
Stomach cancer
TAZ
Transcription factors
Ubiquitin
Wound healing
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Summary:Background The Hippo pathway functions as a tumor suppressor pathway in human cancers, while dysfunction of the Hippo pathway is frequently observed in malignancies. Although YAP/TAZ activity is tightly controlled by the phosphorylation cascade of the MST-LATS-YAP/TAZ axis, it is still unclear why the YAP/TAZ proteins are activated in human cancers despite Hippo pathway activation. Recent studies have suggested that in addition to phosphorylation, several other posttranslational modifications, including ubiquitination, also play critical roles in modulating TAZ function. Methods We used several gastric cancer cell lines and performed western blot analysis, real-time PCR, immunoprecipitation assays, and in vitro ubiquitination assays and established a xenograft mouse model. Results Here, by screening a DUB (deubiquitinase) siRNA library, we discovered that DUB1 functions as a critical modulator that facilitates gastric cancer stemness and progression by deubiquitinating and activating the TAZ protein. We also found that DUB1 expression was elevated in gastric cancer and that elevated DUB1 expression correlated with TAZ activation and poor survival. DUB1 associates with the TAZ protein and deubiquitinates TAZ at several lysine residues, which subsequently stabilizes TAZ and facilitates its function. Conclusions Our study revealed a novel deubiquitinase in the Hippo/TAZ axis and identified one possible therapeutic target for Hippo-driven gastric cancer. Keywords: DUB1, TAZ, Gastric cancer, Deubiquitination, Stabilize
ISSN:1756-9966
0392-9078
1756-9966
DOI:10.1186/s13046-022-02410-5