Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside

Liu, Xiaoli; Wang, Yifei; Chen, Bonan; Chan, Wai Nok; Mui, Chun Wai; Cheung, Alvin Ho‐Kwan; Zhang, Jinglin; Wong, Kit Yee; Yu, Jun; Kang, Wei; To, Ka Fai

doi:10.3390/biomedicines10102512

Cited by 11 publications

(23 citation statements)

References 150 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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“…In lung cancer, SAV1 could bind to zinc fnger protein Gli1 and negatively regulate the Hedgehog signaling pathway [19]. YAP expression was increased in GC, and the Hippo signaling pathway plays a critical role in GC development and progression [6]. Hence, the present study further analyzed the efects of KDM2B on the Hippo signaling pathway in GC.…”

Section: Discussionmentioning

confidence: 86%

“…SAV1 is the core component of the Hippo signaling pathway and suppresses the oncogenic transcriptional module, YAP, which functions as transcriptional coactivators and promotes GC progression [6,7]. KDM2B knockdown led to increased levels of SAV1 protein and YAP phosphorylation and decreased protein levels of YAP and its typical downstream target CTGF (Figure 4(e)).…”

Section: Kdm2b Transcriptionally Inhibits Sav1 Expressionmentioning

confidence: 99%

“…Te phosphorylation of YAP and TAZ can lead to their cytoplasmic translocation, ubiquitination, and degradation. Te cytoplasmic translocation of YAP/TAZ inhibits the transcription of their downstream target oncogenes and leads to tumor suppression [6,7]. SAV1 acts as a tumor suppressor in diferent types of cancer, including pancreatic [8], colon [9], and lung cancer [10].…”

Section: Introductionmentioning

confidence: 99%

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Novel KDM2B/SAV1 Signaling Pathway Promotes the Progression of Gastric Cancer

Song

Chen

et al. 2023

Genetics Research

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Salvador homologue 1 (SAV1), which is reported to act as a tumor suppressor in different types of cancer, is one of the key components of the Hippo pathway. However, the expression and mechanisms of SAV1 in the development and progression of gastric cancer (GC) remain to be elucidated. Immunohistochemistry (IHC) was performed in the present study to assess the expression levels of SAV1 and lysine-specific demethylase 2B (KDM2B) in GC tissues. The biological effects of SAV1 on GC cell proliferation, migration, and invasion were studied in vitro. KDM2B transcriptionally regulates SAV1 expression in several GC cell lines, and molecular experiments were performed to investigate underlying mechanisms. The expression level of SAV1 was significantly decreased in GC tissues and cell lines, negatively associated with tumor invasion depth, lymph node metastasis, and TNM stage, and positively associated with the overall survival of patients with GC. SAV1 overexpression inhibited the proliferation, migration, and invasion of GC cells. Further mechanistic studies revealed that KDM2B transcriptionally regulated SAV1 expression and further regulated the Hippo signaling pathway. To conclude, the present study demonstrated that KDM2B transcriptionally regulated SAV1 expression and promoted GC progression.

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“…5). An updated list of clinical trials on Hippo inhibitors in gastrointestinal cancers has recently been reported elsewhere [131].…”

Section: Targeting Strategiesmentioning

confidence: 99%

Hippo pathway dysregulation in gastric cancer: from Helicobacter pylori infection to tumor promotion and progression

Messina¹,

Sardo²,

Scalera

et al. 2023

Cell Death Dis

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The Hippo pathway plays a critical role for balancing proliferation and differentiation, thus regulating tissue homeostasis. The pathway acts through a kinase cascade whose final effectors are the Yes-associated protein (YAP) and its paralog transcriptional co‑activator with PDZ‑binding motif (TAZ). In response to a variety of upstream signals, YAP and TAZ activate a transcriptional program that modulates cellular proliferation, tissue repair after injury, stem cell fate decision, and cytoskeletal reorganization. Hippo pathway signaling is often dysregulated in gastric cancer and in Helicobacter pylori-induced infection, suggesting a putative role of its deregulation since the early stages of the disease. In this review, we summarize the architecture and regulation of the Hippo pathway and discuss how its dysregulation fuels the onset and progression of gastric cancer. In this setting, we also focus on the crosstalk between Hippo and other established oncogenic signaling pathways. Lastly, we provide insights into the therapeutic approaches targeting aberrant YAP/TAZ activation and discuss the related clinical perspectives and challenges.

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Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside

Cited by 11 publications

References 150 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

Novel KDM2B/SAV1 Signaling Pathway Promotes the Progression of Gastric Cancer

Hippo pathway dysregulation in gastric cancer: from Helicobacter pylori infection to tumor promotion and progression

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