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Ailing W Scott - One of the best experts on this subject based on the ideXlab platform.
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YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition
Gut, 2021Co-Authors: Jaffer A Ajani, Ailing W Scott, Jiankang Jin, Longfei Huo, Melissa Pool Pizzi, Ying Wang, Ruiping Wang, Kazuto Harada, Xiaodan Yao, Wei ZhaoAbstract:Objective Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 (YAP1) oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target. Methods Patient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases. Results YAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1high PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1high PC cells especially in combination with cytotoxics in vivo PDX model. Conclusions YAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.
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YAP1 mediated cdk6 activation confers radiation resistance in esophageal cancer rationale for the combination of YAP1 and cdk4 6 inhibitors in esophageal cancer
Clinical Cancer Research, 2019Co-Authors: Bovey Liu, Ailing W Scott, Pankaj Singh, Wei Zhao, Jiankang Jin, Guangchun Han, Xiaochuan Dong, Longfei Huo, Melissa Pool Pizzi, Ying WangAbstract:Purpose: Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance. Experimental Design: Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacologic and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects in vitro and in vivo. Results: YAP1 expression was positively associated with CDK6 expression in resistant esophageal cancer tissues and cell lines. YAP1 overexpression upregulated CDK6 expression and transcription, and promoted radiation resistance, whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation, as well as sensitized radiation-resistant/YAP1high esophageal cancer cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 dramatically inhibited expression of YAP1 and sensitized resistant esophageal cancer cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. In addition, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced esophageal cancer cell growth and cancer stem cell population (ALDH1+ and CD133+), sensitized cells to irradiation, and showed a strong antitumor effect in vivo against radiation-resistant esophageal cancer cells. Conclusions: Our results document that a positive crosstalk between the YAP1 and CDK6 pathways plays an important role in conferring radiation resistance to esophageal cancer cells. Targeting both YAP1 and CDK6 pathways could be a novel therapeutic strategy to overcome resistance in esophageal cancer.
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a novel YAP1 inhibitor targets csc enriched radiation resistant cells and exerts strong antitumor activity in esophageal adenocarcinoma
Molecular Cancer Therapeutics, 2017Co-Authors: Shumei Song, Ailing W Scott, Jiankang Jin, Xiaochuan Dong, Randy L Johnson, Min Xie, Heath D Skinner, Sheng Ding, Jaffer A AjaniAbstract:Mounting evidence suggests that the Hippo coactivator Yes-associated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma. However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on esophageal adenocarcinoma cell growth especially on YAP1 high-expressing esophageal adenocarcinoma cells both in vitro and in vivo Remarkably, radiation-resistant cells acquire strong cancer stem cell (CSC) properties and aggressive phenotype, while CA3 can effectively suppress these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Furthermore, CA3, combined with 5-FU, synergistically inhibits esophageal adenocarcinoma cell growth especially in YAP1 high esophageal adenocarcinoma cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy-resistant esophageal adenocarcinoma cells endowed with CSC properties. Mol Cancer Ther; 17(2); 443-54. ©2017 AACR.
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the hippo coactivator YAP1 mediates egfr overexpression and confers chemoresistance in esophageal cancer
Clinical Cancer Research, 2015Co-Authors: Shumei Song, Soichiro Honjo, Qiongrong Chen, Ailing W Scott, Wayne L Hofstetter, Jiankang Jin, Shih Shin Chang, Neda Kalhor, Arlene M Correa, Constance AlbarracinAbstract:Purpose:Esophageal cancer (EC) is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of EC patients. However, clinical trials using EGFR inhibitors have not provided benefit for EC patients. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. Experimental Design:In this study, expression of YAP1 and EGFR were examined in EAC resistant tumor tissues vs sensitive tissues by immunohistochemistry. Western blot, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis and in vitro and in vivo functional assays were performed to elucidate the YAP1 mediate EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. Results:We demonstrate that Hippo pathway coactivator YAP1 can induce EGFR expression and transcription in multiple cell systems. Both YAP1 and EGFR are overexpressed in resistant EC tissues compared to sensitive EC tissues. Further, we found that YAP1 increases EGFR expression at the level of transcription requiring an intact TEAD binding site in the EGFR promoter. Most importantly, exogenous induction of YAP1 induces resistance to 5-FU and docetaxcel, while knockdown of YAP sensitizes EC cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. Conclusions:Our data provide evidence that YAP1 up-regulation of EGFR plays an important role in conferring therapy resistance in EC cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in EC.
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hippo coactivator YAP1 upregulates sox9 and endows esophageal cancer cells with stem like properties
Cancer Research, 2014Co-Authors: Shumei Song, Jaffer A Ajani, Soichiro Honjo, Dipen M Maru, Qiongrong Chen, Ailing W Scott, Todd Heallen, Lianchun Xiao, Wayne L Hofstetter, Brian WestonAbstract:Cancer stem cells are proposed to initiate and maintain tumor growth. Deregulation of normal stem cell signaling may lead to the generation of cancer stem cells (CSCs); however, the molecular determinants of this process remain poorly understood. Here we show that the transcriptional co-activator YAP1 is a major determinant of CSC properties in non-transformed cells and in esophageal cancer cells by direct upregulation of SOX9. YAP1 regulates the transcription of SOX9 through a conserved TEAD binding site in the SOX9 promoter. Expression of exogenous YAP1 in vitro or inhibition of its upstream negative regulators in vivo results in elevated SOX9 expression accompanied by the acquisition of CSCs properties. Conversely, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells attenuates CSC phenotypes in vitro and tumorigenecity in vivo. The small molecule inhibitor of YAP1, Verteporfin (VP) significantly blocks CSCs properties in cells with high YAP1 and a high proportion of ALDH1+. Our findings identify YAP1 driven SOX9 expression is a critical event in acquisition of CSC properties, suggesting that YAP1 inhibition may offer an effective means of therapeutically targeting the CSC population.
Jiankang Jin - One of the best experts on this subject based on the ideXlab platform.
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YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition
Gut, 2021Co-Authors: Jaffer A Ajani, Ailing W Scott, Jiankang Jin, Longfei Huo, Melissa Pool Pizzi, Ying Wang, Ruiping Wang, Kazuto Harada, Xiaodan Yao, Wei ZhaoAbstract:Objective Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 (YAP1) oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target. Methods Patient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases. Results YAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1high PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1high PC cells especially in combination with cytotoxics in vivo PDX model. Conclusions YAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.
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YAP1 mediated cdk6 activation confers radiation resistance in esophageal cancer rationale for the combination of YAP1 and cdk4 6 inhibitors in esophageal cancer
Clinical Cancer Research, 2019Co-Authors: Bovey Liu, Ailing W Scott, Pankaj Singh, Wei Zhao, Jiankang Jin, Guangchun Han, Xiaochuan Dong, Longfei Huo, Melissa Pool Pizzi, Ying WangAbstract:Purpose: Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance. Experimental Design: Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacologic and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects in vitro and in vivo. Results: YAP1 expression was positively associated with CDK6 expression in resistant esophageal cancer tissues and cell lines. YAP1 overexpression upregulated CDK6 expression and transcription, and promoted radiation resistance, whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation, as well as sensitized radiation-resistant/YAP1high esophageal cancer cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 dramatically inhibited expression of YAP1 and sensitized resistant esophageal cancer cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. In addition, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced esophageal cancer cell growth and cancer stem cell population (ALDH1+ and CD133+), sensitized cells to irradiation, and showed a strong antitumor effect in vivo against radiation-resistant esophageal cancer cells. Conclusions: Our results document that a positive crosstalk between the YAP1 and CDK6 pathways plays an important role in conferring radiation resistance to esophageal cancer cells. Targeting both YAP1 and CDK6 pathways could be a novel therapeutic strategy to overcome resistance in esophageal cancer.
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a novel YAP1 inhibitor targets csc enriched radiation resistant cells and exerts strong antitumor activity in esophageal adenocarcinoma
Molecular Cancer Therapeutics, 2017Co-Authors: Shumei Song, Ailing W Scott, Jiankang Jin, Xiaochuan Dong, Randy L Johnson, Min Xie, Heath D Skinner, Sheng Ding, Jaffer A AjaniAbstract:Mounting evidence suggests that the Hippo coactivator Yes-associated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma. However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on esophageal adenocarcinoma cell growth especially on YAP1 high-expressing esophageal adenocarcinoma cells both in vitro and in vivo Remarkably, radiation-resistant cells acquire strong cancer stem cell (CSC) properties and aggressive phenotype, while CA3 can effectively suppress these phenotypes by inhibiting proliferation, inducing apoptosis, reducing tumor sphere formation, and reducing the fraction of ALDH1+ cells. Furthermore, CA3, combined with 5-FU, synergistically inhibits esophageal adenocarcinoma cell growth especially in YAP1 high esophageal adenocarcinoma cells. Taken together, these findings demonstrated that CA3 represents a new inhibitor of YAP1 and primarily targets YAP1 high and therapy-resistant esophageal adenocarcinoma cells endowed with CSC properties. Mol Cancer Ther; 17(2); 443-54. ©2017 AACR.
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the hippo coactivator YAP1 mediates egfr overexpression and confers chemoresistance in esophageal cancer
Clinical Cancer Research, 2015Co-Authors: Shumei Song, Soichiro Honjo, Qiongrong Chen, Ailing W Scott, Wayne L Hofstetter, Jiankang Jin, Shih Shin Chang, Neda Kalhor, Arlene M Correa, Constance AlbarracinAbstract:Purpose:Esophageal cancer (EC) is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of EC patients. However, clinical trials using EGFR inhibitors have not provided benefit for EC patients. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. Experimental Design:In this study, expression of YAP1 and EGFR were examined in EAC resistant tumor tissues vs sensitive tissues by immunohistochemistry. Western blot, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis and in vitro and in vivo functional assays were performed to elucidate the YAP1 mediate EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. Results:We demonstrate that Hippo pathway coactivator YAP1 can induce EGFR expression and transcription in multiple cell systems. Both YAP1 and EGFR are overexpressed in resistant EC tissues compared to sensitive EC tissues. Further, we found that YAP1 increases EGFR expression at the level of transcription requiring an intact TEAD binding site in the EGFR promoter. Most importantly, exogenous induction of YAP1 induces resistance to 5-FU and docetaxcel, while knockdown of YAP sensitizes EC cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. Conclusions:Our data provide evidence that YAP1 up-regulation of EGFR plays an important role in conferring therapy resistance in EC cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in EC.
Erik Sahai - One of the best experts on this subject based on the ideXlab platform.
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quantitative analysis reveals that actin and src family kinases regulate nuclear YAP1 and its export
Cell systems, 2018Co-Authors: Nil Ege, Anna M Dowbaj, Ming Jiang, Michael Howell, Steven Hooper, Charles T Foster, Robert P Jenkins, Erik SahaiAbstract:The transcriptional regulator YAP1 is critical for the pathological activation of fibroblasts. In normal fibroblasts, YAP1 is located in the cytoplasm, while in activated cancer-associated fibroblasts, it is nuclear and promotes the expression of genes required for pro-tumorigenic functions. Here, we investigate the dynamics of YAP1 shuttling in normal and activated fibroblasts, using EYFP-YAP1, quantitative photobleaching methods, and mathematical modeling. Imaging of migrating fibroblasts reveals the tight temporal coupling of cell shape change and altered YAP1 localization. Both 14-3-3 and TEAD binding modulate YAP1 shuttling, but neither affects nuclear import. Instead, we find that YAP1 nuclear accumulation in activated fibroblasts results from Src and actomyosin-dependent suppression of phosphorylated YAP1 export. Finally, we show that nuclear-constrained YAP1, upon XPO1 depletion, remains sensitive to blockade of actomyosin function. Together, these data place nuclear export at the center of YAP1 regulation and indicate that the cytoskeleton can regulate YAP1 within the nucleus.
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actin and src family kinases regulate nuclear YAP1 and its export
bioRxiv, 2017Co-Authors: Nil Ege, Anna M Dowbaj, Ming Jiang, Michael Howell, Robert P Jenkins, Erik SahaiAbstract:The transcriptional regulator YAP1 is critical for the pathological activation of fibroblasts. In normal fibroblasts YAP1 is predominantly located in the cytoplasm, while in activated cancer-associated fibroblasts it exhibits nuclear localization and promotes the expression of many genes required for pro-tumorigenic functions. Here, we investigate the dynamics of YAP1 shuttling in normal and activated fibroblasts, using EYFP-YAP1, quantitative photo- bleaching methods, and mathematical modeling. We find that both 14-3-3 and TEAD binding modulate YAP1 shuttling, but neither affects nuclear import. Instead, we find that YAP1 serine phosphorylation is required for nuclear export. Furthermore, YAP1 nuclear accumulation in activated fibroblasts results from Src and actomyosin-dependent suppression of phosphorylated YAP1 export. Finally, we show that nuclear constrained YAP1, upon XPO1 depletion, remains sensitive to blockade of actomyosin function. Together, these data place nuclear export at the center of YAP1 regulation and indicate that the cytoskeleton can regulate YAP1 within the nucleus.
Zhenqiang Sun - One of the best experts on this subject based on the ideXlab platform.
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targeting YAP1 linc00152 fscn1 signaling axis prevents the progression of colorectal cancer
Advanced Science, 2020Co-Authors: Zhenqiang Sun, Songqing Fan, Xiang Zheng, Qiu PengAbstract:As a transcription coactivator, Yes-associated protein 1 (YAP1)'s role in tumorigenesis is well established. However, the mechanism of YAP1-regulating long noncoding RNAs (lncRNA) in tumors is still largely unknown. Here, a YAP1 target gene, long intergenic noncoding RNA 00152 (LINC00152), which is highly expressed in colorectal cancer (CRC), is identified. The oncogenic functions of LINC00152 in CRC are demonstrated by a panel of in vitro and in vivo experiments. Further studies reveal the potential downstream mechanisms of LINC00152, which can act as a competing endogenous RNA sponging with miR-632 and miR-185-3p to regulate Fascin actin-bundling protein 1 (FSCN1) expression and thus promote the malignant proliferation and metastasis in CRC cells. Targeting the YAP1/LINC00152/FSCN1 axis inhibits the progression of CRC. This finding provides a new regulatory model of the "YAP1-lncRNA" in CRC, which gives rise to a new perspective, "YAP1/LINC00152/miR-632-miR-185-3p/FSCN1," to explore the cancer-promoting mechanism of YAP1 involved in CRC.
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YAP1 induced malat1 promotes epithelial mesenchymal transition and angiogenesis by sponging mir 126 5p in colorectal cancer
Oncogene, 2019Co-Authors: Zhenqiang Sun, Jinbo Liu, Chen Chen, Quanbo Zhou, Shuaixi Yang, Guixian Wang, Junmin Song, Zhiyong ZhangAbstract:Yes-associated protein 1 (YAP1) exerts significant effects in various malignancies. However, the oncogenic role of YAP1 remains controversial, and the mechanism by which YAP1 regulates non-coding RNAs is still largely unknown. The present study aimed to assess the effect of YAP1 on the malignant behaviors of colorectal carcinoma (CRC) and explore the underlying regulatory mechanism of the YAP1-MALAT1-miR-126-5p axis. YAP1 was highly expressed in CRC tissues as assessed by GSE20916 and its expression was negatively correlated with overall survival in 83 CRC cases. Meanwhile, YAP1 promoted proliferation, invasion, and migration in colon cancer cells, in vitro and in vivo. MALAT1 was obviously expressed, with differential expression of 11 lncRNAs in HCT116 cells after transfection with siYAP1 or si-Ctl. Based on bioinformatics prediction, immunoprecipitation (IP), and chromatin immunoprecipitation (ChIP), the interaction of YAP1 with TCF4/β-catenin was regulated by MALAT1. Bioinformatics prediction, dual luciferase assay, RNA-IP, and RNA pull-down assay demonstrated that YAP1-induced MALAT1 promoted the expression of metastasis-associated molecules such as VEGFA, SLUG, and TWIST, by sponging miR-126-5p in CRC. These findings indicated that the YAP1-MALAT1-miR-126-5p axis could control angiogenesis and epithelial-mesenchymal transition in CRC, providing potential biomarkers and therapeutic targets for CRC.
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mir 590 5p a density sensitive microrna inhibits tumorigenesis by targeting YAP1 in colorectal cancer
Cancer Letters, 2017Co-Authors: Zhenqiang Sun, Weiguo Ren, Zailong Qin, Xuemei Zhang, Weitang Yuan, Jia Wang, Shiwen Zhang, Qiu Peng, Qun Yan, Wei XiongAbstract:Abstract YAP1, a transcription co-activator, mediates the biological functions of the Hippo pathway. YAP1 inactivation is involved in cell–cell contact inhibition. In various tumors, YAP1 is upregulated through multiple mechanisms, and it functions as an oncogene. Here, we provided evidence that YAP1 influenced multiple signaling pathways in colorectal cancer (CRC) cells. We reported that miR-590-5p directly targets YAP1 and inhibits tumorigenesis in CRC cells both in vitro and in vivo xenograft model. We analyzed different cell densities and found that increased density caused increased expression of miR-590-5p, and decreased expression of its precursors (pri- and pre-miR-590). Increasing cancer cell density upregulated the expression of a RNase III endonuclease, DICER1. DICER1 increased miR-590 biogenesis and inhibited YAP1. In DICER1-defective CRC cells, addition of pre-miR-590 did not inhibit YAP1 expression. Analyses of clinical data demonstrated that the DICER1-miR-590-5p-YAP1 axis was dysregulated in CRC specimens and affected patient survival. Cell–cell contact inhibition is crucial to prevent uncontrolled cell proliferation. Identification of this cell density-sensitive, DICER1-miR-590-5p-YAP1 axis may provide a basis for developing new biomarkers or targeted therapies for CRC.
Hiroshi Sasaki - One of the best experts on this subject based on the ideXlab platform.
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mammalian tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of hippo signaling
Development, 2008Co-Authors: Hiroshi SasakiAbstract:Regulation of organ size is important for development and tissue homeostasis. In Drosophila, Hippo signaling controls organ size by regulating the activity of a TEAD transcription factor, Scalloped, through modulation of its co-activator protein Yki. Here, we show that mouse Tead proteins regulate cell proliferation by mediating Hippo signaling. In NIH3T3 cells, cell density and Hippo signaling regulated the activity of endogenous Tead proteins by modulating nuclear localization of a Yki homolog, YAP1, and the resulting change in Tead activity altered cell proliferation. Tead2-VP16 mimicked YAP1 overexpression, including increased cell proliferation, reduced cell death, promotion of EMT, lack of cell contact inhibition and promotion of tumor formation. Growth-promoting activities of various YAP1 mutants correlated with their Tead-co-activator activities. Tead2-VP16 and YAP1 regulated largely overlapping sets of genes. However, only a few of the Tead/YAP1-regulated genes in NIH3T3 cells were affected in Tead1 -/- ;Tead2 -/- or YAP1 -/- embryos. Most of the previously identified YAP1-regulated genes were not affected in NIH3T3 cells or mutant mice. In embryos, levels of nuclear YAP1 and Tead1 varied depending on cell type. Strong nuclear accumulation of YAP1 and Tead1 were seen in myocardium, correlating with requirements of Tead1 for proliferation. However, their distribution did not always correlate with proliferation. Taken together, mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling, but the mechanisms by which Tead/YAP1 regulate cell proliferation differ depending on the cell type, and Tead, YAP1 and Hippo signaling may play multiple roles in mouse embryos.
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mammalian tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of hippo signaling
Development, 2008Co-Authors: Hiroshi SasakiAbstract:Regulation of organ size is important for development and tissue homeostasis. In Drosophila, Hippo signaling controls organ size by regulating the activity of a TEAD transcription factor, Scalloped, through modulation of its co-activator protein Yki. Here, we show that mouse Tead proteins regulate cell proliferation by mediating Hippo signaling. In NIH3T3 cells, cell density and Hippo signaling regulated the activity of endogenous Tead proteins by modulating nuclear localization of a Yki homolog, YAP1, and the resulting change in Tead activity altered cell proliferation. Tead2-VP16 mimicked YAP1 overexpression, including increased cell proliferation, reduced cell death, promotion of EMT, lack of cell contact inhibition and promotion of tumor formation. Growth-promoting activities of various YAP1 mutants correlated with their Tead-co-activator activities. Tead2-VP16 and YAP1 regulated largely overlapping sets of genes. However, only a few of the Tead/YAP1-regulated genes in NIH3T3 cells were affected in Tead1 -/- ;Tead2 -/- or YAP1 -/- embryos. Most of the previously identified YAP1-regulated genes were not affected in NIH3T3 cells or mutant mice. In embryos, levels of nuclear YAP1 and Tead1 varied depending on cell type. Strong nuclear accumulation of YAP1 and Tead1 were seen in myocardium, correlating with requirements of Tead1 for proliferation. However, their distribution did not always correlate with proliferation. Taken together, mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling, but the mechanisms by which Tead/YAP1 regulate cell proliferation differ depending on the cell type, and Tead, YAP1 and Hippo signaling may play multiple roles in mouse embryos.
