scholarly journals MINDY1 promotes bladder cancer progression by stabilizing YAP

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yongwen Luo ◽  
Jun Zhou ◽  
Jianing Tang ◽  
Fengfang Zhou ◽  
Zhiwen He ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Tumor Model ◽  
Dependent Manner ◽  
Interaction Domain ◽  
Bona Fide ◽  
The Hippo Pathway

Abstract Background Bladder cancer is one of the most commonly diagnosed urological malignant tumor. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in bladder cancer remains to be characterized. Methods Western blot was used to measure the expression of MINDY1 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect the cell viability. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between MINDY1 and YAP. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. Results In the present study, we identified MINDY1, a DUB enzyme in the motif interacting with ubiquitin-containing novel DUB family, as a bona fide deubiquitylase of YAP in bladder cancer. MINDY1 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. MINDY1 depletion significantly decreased bladder cancer cell proliferation. The effects induced by MINDY1 depletion could be rescued by further YAP overexpression. Depletion of MINDY1 decreased the YAP protein level and the expression of YAP/TEAD target genes in bladder cancer, including CTGF, ANKRD1 and CYR61. Conclusion In general, our findings establish a previously undocumented catalytic role for MINDY1 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of bladder cancer.

scholarly journals TRIM11 promotes the proliferation, migration and chemoresistance of anaplastic thyroid cancer by stabilizing YAP

2020 ◽  
Author(s):  
Jianing Tang ◽  
Zelin Tian ◽  
Xing Liao ◽  
Qiuxia Cui ◽  
Gaosong Wu
Keyword(s):  
Thyroid Cancer ◽  
Target Genes ◽  
Hippo Pathway ◽  
Tumor Model ◽  
Anaplastic Thyroid Cancer ◽  
Ubiquitin Proteasome System ◽  
Migration Ability ◽  
Interaction Domain ◽  
Oncogenic Function

Abstract Background Anaplastic thyroid cancer (ATC) is one of the most aggressive and virulent solid tumors. The ubiquitin proteasome system presents in all eukaryotic cells and is essential for cellular homeostasis. While its underlying role in ATC remains largely unclear. TRIM11 is an E3 ubiquitin ligase and has been reported to act as an oncogene in several human cancers. The present study aims to reveal the oncogenic function of TRIM11 in ATC. Methods Western blot was used to measure the protein expression of TRIM11 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; wound-healing assay and transwell assay were used to measure the migration ability of ATC. The xeno-graft tumor model was used for in vivo study. RNA sequencing was analyzed by Ingenuity Pathway Analysis. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and TRIM11. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. Results TRIM11 depletion significantly decreases cell proliferation and migration capabilities of ATC cells, and elevates cell sensitivity to chemotherapy. The effects induced by TRIM11 depletion could be rescued by further YAP overexpression. Depletion TRIM11 decreases YAP protein level and YAP/TEAD target genes, such as CTGF, ANKRD1 and CYR61 in ATC. Immuno-precipitation assay shows that TRIM11 associates with YAP, promoting YAP stabilization possibly via inducing YAP mono-ubiquitination. Further mechanistic analysis indicates that the RING domain of TRIM11 interacts with the WW domain of YAP and promotes its mono-ubiquitination, thus prolongs YAP protein half. Conclusions Our study describes the oncogenic function of TRIM11 in ATC, which acts as a post-translational modulating factor of Hippo pathway. Targeting TRIM11 could be a promising therapeutic method for ATC treatment.

scholarly journals YAP manipulates proliferation via PTEN/AKT/mTOR-mediated autophagy in lung adenocarcinomas

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Xu ◽  
Mingjiong Zhang ◽  
Yue Li ◽  
Yu Wang ◽  
Kai Wang ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Tumor Model ◽  
Gene Expression Omnibus ◽  
Dependent Manner ◽  
Xenograft Tumor Model ◽  
Lung Adenocarcinomas ◽  
The Hippo Pathway ◽  
Inhibitor Treatment

Abstract Background Autophagy is a double-edged sword during the initiation and progression of multiple tumors. The Hippo pathway effector YAP has been proved to be involved in autophagy processes. The present study aimed to investigate how YAP regulates cell proliferation via autophagy in lung adenocarcinomas (LUAD). Methods Data of LUAD chip GSE43458 was obtained from Gene Expression Omnibus (GEO). RT-qPCR and Western blot were performed to assess YAP expression in LUAD cell lines. CCK-8 assay, xenograft tumor model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on autophagy of LUAD cells in vitro and in vivo. Autophagy inhibitor treatment and rescue experiments were carried out to elucidate the mechanism by which YAP manipulates autophagy in LUAD cells. Results YAP was significantly overexpressed in samples of LUAD patients and its expression level is related to 5-year survival. YAP manipulated the proliferation and autophagy in A549 and H1299 LUAD cells. YAP could induce activation of Akt/mTOR signaling pathway via suppressing PTEN in a Hippo-pathway-dependent manner. 3-Methyladenine impeded autophagy flux and promoted the proliferation in vitro and in vivo. Conclusions Hippo pathway critical transcriptional coactivators YAP manipulates the proliferation of lung adenocarcinoma, which is regulated by PTEN/AKT/mTOR autophagic signaling.

scholarly journals NUSAP1 Promotes Gastric Cancer Progression Through Regulation of Yap Stability

2020 ◽  
Author(s):  
Hui Guo ◽  
Jianping Zou ◽  
Ling Zhou ◽  
Yan He ◽  
Miao Feng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Critical Role ◽  
Xenograft Model ◽  
Migration And Invasion

Abstract Background:Nucleolar and spindle associated protein (NUSAP1) is involved in tumor initiation, progression and metastasis. However, there are limited studies regarding the role of NUSAP1 in gastric cancer (GC). Methods: The expression profile and clinical significance of NUSAP1 in GC were analysed in online database using GEPIA, Oncomine and KM plotter, which was further confirmed in clinical specimens.The functional role of NUSAP1 were detected utilizing in vitro and in vivo assays. Western blotting, qRT-PCR, the cycloheximide-chase, immunofluorescence staining and Co-immunoprecipitaion (Co-IP) assays were performed to explore the possible molecular mechanism by which NUSAP1 stabilizes YAP protein. Results:In this study, we found that the expression of NUSAP1 was upregulated in GC tissues and correlates closely with progression and prognosis. Additionally, abnormal NUSAP1 expression promoted malignant behaviors of GC cells in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 physically interacts with YAP and furthermore stabilizes YAP protein expression, which induces the transcription of Hippo pathway downstream target genes. Furthermore, the effects of NUSAP1 on GC cell growth, migration and invasion were mainly mediated by YAP. Conclusions:Our data demonstrates that the novel NUSAP1-YAP axis exerts an critical role in GC tumorigenesis and progression, and therefore could provide a novel therapeutic target for GC treatment.

scholarly journals Exosomal miR-1290 promotes angiogenesis in hepatocellular carcinoma via targeting SMEK1

2019 ◽  
Author(s):  
Qiong Wang ◽  
Guanwen Wang ◽  
Lianjie Niu ◽  
Shaorong Zhao ◽  
Jianjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endothelial Cells ◽  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Primary Liver Cancer ◽  
Tumor Model ◽  
Luciferase Reporter ◽  
Dependent Manner

Abstract Abstract Background: Hepatocellular carcinoma (HCC), the most common primary liver cancer, rely on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. Methods: MiRNome sequencing was performed to uncover the miRNAs that are dysregulated in HCC patient serum-derived exosomes. Expression levels of miR-1290 in tissues and cells were determined by quantitative real-time PCR. The effect of mir-1290 on proliferation was evaluated by CCK-8 assay. The angiogenic ability of cells were determined by transwell, wound-healing, tube formation and matrigel plug assays. SMMC-7721 xenograft tumor model was established in NOD-SCID nude mice using miR-1290 and NC antagomirs to determin the angiogenic effect of mir-1290 in vivo. Target protein expression was determined by western blotting. Dual luciferase reporter assay was performed to confirm the action of miR-1290 on downstream target genes including SMEK1. Results are reported as means ± S.D. and differences were tested for significance using 2-sided Student’s t-test. Results: In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its pro-angiogenic function, at least in part, by inhibiting the VEGFR2 signaling pathway in a SMEK1-dependent manner. Conclusions: Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.

scholarly journals α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis

2021 ◽  
Vol 134 (8) ◽  
Author(s):  
Aleena K. S. Arakaki ◽  
Wen-An Pan ◽  
Helen Wedegaertner ◽  
Ivette Roca-Mercado ◽  
Logan Chinn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Hippo Pathway ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
The Hippo Pathway

ABSTRACT The α-arrestin domain containing protein 3 (ARRDC3) is a tumor suppressor in triple-negative breast carcinoma (TNBC), a highly metastatic subtype of breast cancer that lacks targeted therapies. Thus, understanding the mechanisms and targets of ARRDC3 in TNBC is important. ARRDC3 regulates trafficking of protease-activated receptor 1 (PAR1, also known as F2R), a G-protein-coupled receptor (GPCR) implicated in breast cancer metastasis. Loss of ARRDC3 causes overexpression of PAR1 and aberrant signaling. Moreover, dysregulation of GPCR-induced Hippo signaling is associated with breast cancer progression. However, the mechanisms responsible for Hippo dysregulation remain unknown. Here, we report that the Hippo pathway transcriptional co-activator TAZ (also known as WWTR1) is the major effector of GPCR signaling and is required for TNBC migration and invasion. Additionally, ARRDC3 suppresses PAR1-induced Hippo signaling via sequestration of TAZ, which occurs independently of ARRDC3-regulated PAR1 trafficking. The ARRDC3 C-terminal PPXY motifs and TAZ WW domain are crucial for this interaction and are required for suppression of TNBC migration and lung metastasis in vivo. These studies are the first to demonstrate a role for ARRDC3 in regulating GPCR-induced TAZ activity in TNBC and reveal multi-faceted tumor suppressor functions of ARRDC3. This article has an associated First Person interview with the first author of the paper.

scholarly journals Usp10 Modulates the Hippo Pathway by Deubiquitinating and Stabilizing the Transcriptional Coactivator Yorkie

2019 ◽  
Vol 20 (23) ◽  
pp. 6013
Author(s):  
Yang Gao ◽  
Xiaoting Zhang ◽  
Lijuan Xiao ◽  
Chaojun Zhai ◽  
Tao Yi ◽  
...  
Keyword(s):  
Target Genes ◽  
Hippo Pathway ◽  
Size Control ◽  
Deubiquitinating Enzyme ◽  
Hippo Signaling ◽  
Evolutionarily Conserved ◽  
Specific Protease ◽  
Wing Discs ◽  
The Hippo Pathway

The Hippo signaling pathway is an evolutionarily conserved regulator that plays important roles in organ size control, homeostasis, and tumorigenesis. As the key effector of the Hippo pathway, Yorkie (Yki) binds to transcription factor Scalloped (Sd) and promotes the expression of target genes, leading to cell proliferation and inhibition of apoptosis. Thus, it is of great significance to understand the regulatory mechanism for Yki protein turnover. Here, we provide evidence that the deubiquitinating enzyme ubiquitin-specific protease 10 (Usp10) binds Yki to counteract Yki ubiquitination and stabilize Yki protein in Drosophila S2 cells. The results in Drosophila wing discs indicate that silence of Usp10 decreases the transcription of target genes of the Hippo pathway by reducing Yki protein. In vivo functional analysis ulteriorly showed that Usp10 upregulates the Yki activity in Drosophila eyes. These findings uncover Usp10 as a novel Hippo pathway modulator and provide a new insight into the regulation of Yki protein stability and activity.

scholarly journals Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Sandra Muñoz-Galván ◽  
Blanca Felipe-Abrio ◽  
Eva M. Verdugo-Sivianes ◽  
Marco Perez ◽  
Manuel P. Jiménez-García ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Hippo Pathway ◽  
Ovarian Tumors ◽  
Tumor Resistance ◽  
Functional Link ◽  
The Hippo Pathway

Abstract Background Ovarian cancer is one of the most common and malignant cancers, partly due to its late diagnosis and high recurrence. Chemotherapy resistance has been linked to poor prognosis and is believed to be linked to the cancer stem cell (CSC) pool. Therefore, elucidating the molecular mechanisms mediating therapy resistance is essential to finding new targets for therapy-resistant tumors. Methods shRNA depletion of MYPT1 in ovarian cancer cell lines, miRNA overexpression, RT-qPCR analysis, patient tumor samples, cell line- and tumorsphere-derived xenografts, in vitro and in vivo treatments, analysis of data from ovarian tumors in public transcriptomic patient databases and in-house patient cohorts. Results We show that MYPT1 (PPP1R12A), encoding myosin phosphatase target subunit 1, is downregulated in ovarian tumors, leading to reduced survival and increased tumorigenesis, as well as resistance to platinum-based therapy. Similarly, overexpression of miR-30b targeting MYPT1 results in enhanced CSC-like properties in ovarian tumor cells and is connected to the activation of the Hippo pathway. Inhibition of the Hippo pathway transcriptional co-activator YAP suppresses the resistance to platinum-based therapy induced by either low MYPT1 expression or miR-30b overexpression, both in vitro and in vivo. Conclusions Our work provides a functional link between the resistance to chemotherapy in ovarian tumors and the increase in the CSC pool that results from the activation of the Hippo pathway target genes upon MYPT1 downregulation. Combination therapy with cisplatin and YAP inhibitors suppresses MYPT1-induced resistance, demonstrating the possibility of using this treatment in patients with low MYPT1 expression, who are likely to be resistant to platinum-based therapy.

EXTH-04. ELUCIDATING THE PLEIOTROPIC EFFECTS OF VERTEPORFIN PHOTODYNAMIC THERAPY IN PRECLINICAL GLIOBLASTOMA MODELS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi164-vi164
Author(s):  
Gabrielle Price ◽  
Sweta Sudhir ◽  
Concetta Brusco ◽  
Alexandros Bouras ◽  
Nadejda Tsankova ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Factor Receptor ◽  
Therapy Resistance ◽  
Antitumor Effects ◽  
Cell Dynamics ◽  
The Hippo Pathway

Abstract Glioblastoma (GBM) has the highest mortality rate, incidence, and therapy resistance of all primary brain tumors. Deregulation of the epidermal growth factor receptor (EGFR) has been implicated in GBM tumorigenesis. The expression of EGFR has been linked to hippo pathway transcriptional co-activators YAP and TAZ that bind to TEAD co-factors to drive the transcription of target genes. The convergence of EGFR signaling and the hippo pathway regulates stem cell programs, including proliferation, survival, and self-renewal. Verteporfin (VP), is an FDA-approved drug for photodynamic therapy (PDT) of macular degeneration. VP has been shown to have antitumor effects both in vitro and in vivo in GBM preclinical models. As a porphyrin derivative, VP can also exert therapeutic and photodynamic effects in the presence of 689 nm light; however, the efficacy of VP-PDT has not been explored in GBM. Our results indicate for the first time that VP-PDT reduces GBM cell viability to a greater extent than VP treatment alone (viability — 0.7 uM VP: 97%, 0.7 uM VP-PDT: 46%). The antitumor effects of VP-PDT are two pronged involving 1) inhibition of live cell dynamics, including migration and intravasation, by downregulating hippo pathway constituents YAP, TAZ and TEAD and transcriptional target EGFR and 2) induction of programmed cell death by reactive oxygen species. Our results suggest that VP-PDT can be a potential avenue for treating these incurable tumors.

scholarly journals Targeting IRF3 as a YAP agonist therapy against gastric cancer

2018 ◽  
Vol 215 (2) ◽  
pp. 699-718 ◽  
Author(s):  
Shi Jiao ◽  
Jingmin Guan ◽  
Min Chen ◽  
Wenjia Wang ◽  
Chuanchuan Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Patient Survival ◽  
Hippo Pathway ◽  
Vital Role ◽  
Dependent Manner ◽  
Genome Wide ◽  
The Hippo Pathway ◽  
Innate Antiviral Immunity

The Hippo pathway plays a vital role in tissue homeostasis and tumorigenesis. The transcription factor IRF3 is essential for innate antiviral immunity. In this study, we discovered IRF3 as an agonist of Yes-associated protein (YAP). The expression of IRF3 is positively correlated with that of YAP and its target genes in gastric cancer; the expression of both IRF3 and YAP is up-regulated and prognosticates patient survival. IRF3 interacts with both YAP and TEAD4 in the nucleus to enhance their interaction, promoting nuclear translocation and activation of YAP. IRF3 and YAP–TEAD4 are associated genome-wide to cobind and coregulate many target genes of the Hippo pathway. Overexpression of active IRF3 increased, but depletion of IRF3 reduced, the occupancy of YAP on the target genes. Knockdown or pharmacological targeting of IRF3 by Amlexanox, a drug used clinically for antiinflammatory treatment, inhibits gastric tumor growth in a YAP-dependent manner. Collectively, our study identifies IRF3 as a positive regulator for YAP, highlighting a new therapeutic target against YAP-driven cancers.

scholarly journals YAP Manipulates Proliferation Via PTEN/AKT/mTOR-mediated Autophagy in Lung Adenocarcinomas

2020 ◽  
Author(s):  
Wei Xu ◽  
Mingjiong Zhang ◽  
Yue Li ◽  
Yu Wang ◽  
Kai Wang ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Tumor Model ◽  
Gene Expression Omnibus ◽  
Dependent Manner ◽  
Autophagy Flux ◽  
Xenograft Tumor Model ◽  
Lung Adenocarcinomas ◽  
Proliferation In Vitro

Abstract Background: Autophagy is a double-edged sword during the initiation or progression of multiple tumors. Hippo pathway core-factor YAP has been proved to be involved in autophagy processes. The present study aimed to identify the mechanism underlying modulation of YAP via PTEN/AKT/mTOR-mediated autophagy in lung adenocarcinomas (LUAD).Methods: Data of LUAD chip GSE43458 was obtained from Gene Expression Omnibus (GEO). RT-qPCR and Western blot were used to assess YAP expression in LUAD cell lines. CCK-8 assay, flow cytometry, xenograft tumor model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on autophagy of LUAD cells in vitro and in vivo. Autophagy inhibitor and rescue experiments were carried out to elucidate the mechanism by which YAP manipulating autophagy in LUAD cells.Results: YAP significantly overexpressed in samples of LUAD patients and related to 5-year survival. YAP manipulates the proliferation and autophagy of A549 and H1299 LUAD cells. YAP induces activation of Akt/mTOR signaling pathway via suppressing PTEN in a Hippo-pathway-dependent manner. 3-Methyladenine impeded autophagy flux and promoted the proliferation in vitro and in vivo.Conclusions: Hippo pathway critical transcriptional coactivators YAP manipulates the proliferation of lung adenocarcinoma, which is regulated by PTEN/AKT/mTOR autophagic signaling.

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