Targeting <scp>YAP1</scp>/<scp>TAZ</scp> in nonsmall‐cell lung carcinoma: From molecular mechanisms to precision medicine

Mui, Chun Wai; Chan, Wai Nok; Chen, Bonan; Cheung, Alvin Ho‐Kwan; Yu, Jun; Lo, Kwok Wai; Huixing, Ke; Kang, Wei; To, Ka Fai

doi:10.1002/ijc.34249

Cited by 13 publications

(7 citation statements)

References 134 publications

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“…YAP1, a transcriptional regulator, is widely activated in various human malignancies, including GBC [ 34 , 37 , 38 ]. Studies have shown that YAP/TAZ plays an essential role in cancer initiation or growth of most solid tumors [ 39 , 40 ]. YAP1 interacts with the PPxY motif via its WW domains, leading to post-transcriptional modifications (PTMs) at different sites, contributing to its stability and spatial regulation [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

The oncogenic role of NF1 in gallbladder cancer through regulation of YAP1 stability by direct interaction with YAP1

et al. 2023

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Background Gallbladder cancer (GBC) is the most prevalent and invasive biliary tract malignancy. As a GTPase-activating protein, Neurofibromin 1 (NF1) is a tumor suppressor that negatively regulates the RAS signaling pathway, and its abnormality leads to neurofibromatosis type 1 (NF-1) disease. However, the role of NF1 playing in GBC and the underlying molecular mechanism has not been defined yet. Methods A combination of NOZ and EH-GB1 cell lines as well as nude mice, were utilized in this study. mRNA expression and protein levels of NF1 and YAP1 were evaluated by quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC). In vitro and in vivo assays were performed to explore the biological effects of NF1 in NOZ and EH-GB1 cells via siRNA or lv-shRNA mediated knockdown. Direct interaction between NF1 and YAP1 was detected by confocal microscopy and co-immunoprecipitation (Co-IP), and further confirmed by GST pull-down assay and isothermal titration calorimetry assay (ITC). The stability of proteins was measured by western blot (WB) in the presence of cycloheximide. Results This study showed that a higher level of NF1 and YAP1 was found in GBC samples than in normal tissues and associated with worse prognoses. The NF1 knockdown impaired the proliferation and migration of NOZ in vivo and in vitro by downregulating YAP1 expression. Moreover, NF1 co-localized with YAP1 in NOZ and EH-GB1 cells, and the WW domains of YAP1 specifically recognized the PPQY motif of NF1. The structural modeling also indicated the hydrophobic interactions between YAP1 and NF1. On the other hand, YAP1 knockdown also impaired the proliferation of NOZ in vitro, phenocopying the effects of NF1 knockdown. Overexpression of YAP1 can partially rescue the impaired proliferation in NF1 stably knockdown cells. In mechanism, NF1 interacted with YAP1 and increased the stability of YAP1 by preventing ubiquitination. Conclusions Our findings discovered a novel oncogenic function of NF1 by directly interacting with YAP1 protein and stabilizing YAP1 to protect it from proteasome degradation in NOZ cells. NF1 may serve as a potential therapeutic target in GBC.

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Section: Discussionmentioning

confidence: 99%

The oncogenic role of NF1 in gallbladder cancer through regulation of YAP1 stability by direct interaction with YAP1

et al. 2023

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“…Dysregulated YAP activity has been strongly associated with the development of cancer 38,41 . Elevated YAP expression has been observed in oral, breast, lung, and liver cancers 42–45 . In HNSCC, frequent deletion or truncation of FAT1 disperses Hippo components and leads to aberrant activation of YAP via suppressing its ubiquitination 46 .…”

Section: Discussionmentioning

confidence: 99%

“… 38 , 41 Elevated YAP expression has been observed in oral, breast, lung, and liver cancers. 42 , 43 , 44 , 45 In HNSCC, frequent deletion or truncation of FAT1 disperses Hippo components and leads to aberrant activation of YAP via suppressing its ubiquitination. 46 As gene alterations of FAT1 is frequently occurred in HNSCC, 47 FAT1 gene alterations may be involved in the prevalent YAP activation in HNSCC.…”

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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“…The migration of cancer cells is a main cause of increased cancer deaths [35,36]. The in vitro wound scratch tests were utilised to examine the migration and invasion of L929 cells and A549 cells against chaetocin.…”

Section: Assessment Of Migration and Invasion Of L929 And A549 Cellsmentioning

confidence: 99%

Natural compound chaetocin induced DNA damage and apoptosis through reactive oxygen species‐dependent pathways in A549 lung cancer cells and in vitro evaluations

Zhang

Ruan

Yang³

et al. 2023

IET Nanobiotechnology

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There is an urgent need for potential pharmaceutics for lung cancer treatment due to the increased number of lung cancer deaths and the resistance of cancer cells to present therapeutics. The present work aims to discover the anticancer potential of the natural compound chaetocin as a therapeutic for lung cancer treatment. Results showed the significance of chaetocin-induced cell growth inhibition by the expression of G 2 /M phase arrest and reactive oxygen species (ROS) dependent apoptosis in A549 lung cancer cells. Results concluded that chaetocin could produce ROS and nuclear damage against A549 lung cancer cells. Interestingly, chaetocin exhibits a significant level of CD47 that downregulates the expression of CD47 at mRNA levels. PBMC biocompatibility study revealed that chaetocin is non-toxic to normal cells. Overall, experimental results suggested that chaetocin induces A549 cell apoptosis, by causing ROS and nuclear damage activation pathways. In the future, chaetocin might be an effective bio-safe anticancer agent for lung cancer treatments.

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Targeting YAP1/TAZ in nonsmall‐cell lung carcinoma: From molecular mechanisms to precision medicine

Cited by 13 publications

References 134 publications

The oncogenic role of NF1 in gallbladder cancer through regulation of YAP1 stability by direct interaction with YAP1

The oncogenic role of NF1 in gallbladder cancer through regulation of YAP1 stability by direct interaction with YAP1

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

Natural compound chaetocin induced DNA damage and apoptosis through reactive oxygen species‐dependent pathways in A549 lung cancer cells and in vitro evaluations

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