The Hippo/YAP1 pathway interacts with FGFR1 signaling to maintain stemness in lung cancer

Lü, Tingting; Li, Ziming; Yang, Ying; Ji, Wei; Ye, Yu; Niu, Xiaomin; Zeng, Qingyu; Xia, Weiliang; Lu, Shun

doi:10.1016/j.canlet.2018.02.015

Cited by 66 publications

(58 citation statements)

References 47 publications

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“…Hippo-YAP1 signaling is among the most prominent intracellular pathways in gastric carcinogenesis. Hippo functions as a tumor suppressor in GC, which is concordant with other cancer types [18][19][20]. Our previous works have delineated the role of YAP1 in GC and its regulation from the post-translational level [11,12].…”

Section: Discussionsupporting

confidence: 60%

AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis

Zhou

Zhang

et al. 2020

Oncogene

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Hippo signaling functions to limit cellular growth, but the aberrant nuclear accumulation of its downstream YAP1 leads to carcinogenesis. YAP1/TEAD complex activates the oncogenic downstream transcription, such as CTGF and c-Myc. How YAP1 is protected in the cytoplasm from ubiquitin-mediated degradation remains elusive. In this study, a member of Angiomotin (Motin) family, AMOTL1 (Angiomotin Like 1), was screened out as the only one to promote YAP1 nuclear accumulation by several clinical cohorts, which was further confirmed by the cellular functional assays. The interaction between YAP1 and AMOTL1 was suggested by co-immunoprecipitation and immunofluorescent staining. The clinical significance of the AMOTL1-YAP1-CTGF axis in gastric cancer (GC) was analyzed by multiple clinical cohorts. Moreover, the therapeutic effect of targeting the oncogenic axis was appraised by drug-sensitivity tests and xenograftformation assays. The upregulation of AMOTL1 is associated with unfavorable clinical outcomes of GC, and knocking down AMOTL1 impairs its oncogenic properties. The cytoplasmic interaction between AMOTL1 and YAP1 protects each other from ubiquitin-mediated degradation. AMOTL1 promotes YAP1 translocation into the nuclei to activate the downstream expression, such as CTGF. Knocking down AMOTL1, YAP1, and CTGF enhances the therapeutic efficacies of the first-line anticancer drugs. Taken together, AMOTL1 plays an oncogenic role in gastric carcinogenesis through interacting with YAP1 and promoting its nuclear accumulation. A combination of AMOTL1, YAP1, and CTGF expression might serve as a surrogate of Hippo activation status. The co-activation of the AMOTL1/YAP1-CTGF axis is associated with poor clinical outcomes of GC patients, and targeting this oncogenic axis may enhance the chemotherapeutic effects.

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Section: Discussionsupporting

confidence: 60%

AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis

Zhou

Zhang

et al. 2020

Oncogene

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“…VP treatment led to YAP, AXL, CYR61 and/or CTGF downregulation in different subtypes of BC cell lines, suggesting that these effectors could be their own target genes as described in MDA-MB-231 cells [28][29][30] initially regarded as an FDA-approved photo-sensitizer drug in photodynamic treatment, VP has been described as having anti-tumor behaviors by preventing YAP-TEAD connection [34]. In agreement with prior studies that showed that VP suppressed proliferation of lung tumor [35], prostate tumor [36] and mesothelioma tumor [37], our results show that VP also inhibited the proliferation of Luminal A MCF-7,…”

Section: Verteporfin Induces Cell Apoptosis By Disrupting Yap-tead Cosupporting

confidence: 85%

Verteporfin Inhibits Cell Proliferation and Induces Apoptosis in Different Subtypes of Breast Cancer Cell Lines Without Light Activation

Wei

2020

Preprint

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Background Breast cancer (BC) can be separated into four molecular subclassifications including Lumina1 A, Lumina1 B, HER-2 overexpression and Basal-like subtype. These classifications are based on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2) and cell proliferation antigen (Ki-67). The Hippo signaling pathway plays an indispensable role in BC. The YAP1 gene is a terminal effector of Hippo pathway, and hyperactivation of YAP mediates tumorigenesis. As an inhibitor of YAP, non-photoactivated verteporfin (VP) can inhibit YAP-mediated tumor proliferation and angiogenesis by eliminating its interaction with TEAD. This study set out to determine the effect and molecular mechanisms of VP-mediated inhibition of YAP in different subtypes of BC. Methods Luminal A, Luminal B and Basal-like BC cells were cultivated in vitro in order to study effect of VP on proliferation and apoptosis on these three molecular BC subtypes. Results Our experimental results show that VP inhibits cell proliferation, YAP-TEAD interaction and its downstream target expression. VP also induces tumor cell apoptosis, and promotes the cleavage of Caspase-9 and PARP in various molecular subtypes of BC cells. Conclusion These findings provide a basis for VP as a potential anti-tumor therapeutic for BC by targeting the Hippo pathway effector YAP.

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“…Consequently, LINC00519 knock‐down decreased only YAP1 protein level but failed to alter the levels of MST1/2, p‐MST1/2 and p‐YAP1 (Figure 4B and Figure B), indicating that LINC00519 positively regulated YAP1. YAP1 is a pivotal factor in Hippo pathway, and when Hippo signalling is turned off, YAP1 is activated to elicit carcinogenic functions in cancers including lung cancer 22,23. High YAP1 expression in LUSC tissues was confirmed (Figure 4C).…”

Section: Resultsmentioning

confidence: 76%

H3K27ac‐activated LINC00519 promotes lung squamous cell carcinoma progression by targeting miR‐450b‐5p/miR‐515‐5p/YAP1 axis

Rusidanmu

et al. 2020

Cell Proliferation

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Objectives Long non‐coding RNAs (lncRNAs) are extensively reported as participants in the biological process of diverse malignancies, including lung squamous cell carcinoma (LUSC). Long intergenic non‐protein coding RNA 519 (LINC00519) is identified as a novel lncRNA which has not yet been studied in cancers. Materials and Methods LINC00519 expression was detected by qRT‐PCR. The effect of LINC00519 on LUSC cellular activities was determined by in vitro and in vivo assays. Subcellular fractionation and FISH assays were conducted to identify the localization of LINC00519. The interaction between miR‐450b‐5p/miR‐515‐5p and LINC00519/YAP1 was verified by RIP, RNA pull‐down and luciferase reporter assays. Results Elevated level of LINC00519 was identified in LUSC tissues and cell lines. High LINC00519 level predicted unsatisfactory prognosis. Then, loss‐of‐function assays suggested the inhibitive role of silenced LINC00519 in cell proliferation, migration, invasion and tumour growth and promoting effect on cell apoptosis in LUSC. Mechanically, LINC00519 was activated by H3K27 acetylation (H3K27ac). Moreover, LINC00519 sponged miR‐450b‐5p and miR‐515‐5p to up‐regulate Yes1 associated transcriptional regulator (YAP1). Additionally, miR‐450b‐5p and miR‐515‐5p elicited anti‐carcinogenic effects in LUSC. Finally, rescue assays validated the effect of LINC00519‐miR‐450b‐5p‐miR‐515‐5p‐YAP1 axis in LUSC. Conclusions H3K27ac‐activated LINC00519 acts as a competing endogenous RNA (ceRNA) to promote LUSC progression by targeting miR‐450b‐5p/miR‐515‐5p/YAP1 axis.

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The Hippo/YAP1 pathway interacts with FGFR1 signaling to maintain stemness in lung cancer

Cited by 66 publications

References 47 publications

AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis

AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis

Verteporfin Inhibits Cell Proliferation and Induces Apoptosis in Different Subtypes of Breast Cancer Cell Lines Without Light Activation

H3K27ac‐activated LINC00519 promotes lung squamous cell carcinoma progression by targeting miR‐450b‐5p/miR‐515‐5p/YAP1 axis

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