STUB1 suppresseses tumorigenesis and chemoresistance through antagonizing YAP1 signaling

Yes‐associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in...

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Vydáno v:	Cancer science Ročník 110; číslo 10; s. 3145 - 3156
Hlavní autoři:	Tang, Dong‐E, Dai, Yong, Lin, Lie‐Wen, Xu, Yong, Liu, Dong‐Zhou, Hong, Xiao‐Ping, Jiang, Hao‐Wu, Xu, Song‐Hui
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England John Wiley & Sons, Inc 01.10.2019 John Wiley and Sons Inc
Témata:	Adaptor Proteins, Signal Transducing - chemistry Adaptor Proteins, Signal Transducing - metabolism Animals Carcinogenesis Cell growth Cell Line, Tumor Cell Proliferation Cell survival Chemoresistance Drug Resistance, Neoplasm Female Gastric cancer Gene Expression Regulation, Neoplastic HEK293 Cells Humans Kinases Lysine - metabolism Mass spectrometry Medical prognosis Mice Mutation Neoplasm Transplantation Original Peptides Phosphoproteins - chemistry Phosphoproteins - metabolism Plasmids Protein Stability Proteins Proteolysis Scientific imaging Signal Transduction Statistical analysis Stomach Neoplasms - drug therapy Stomach Neoplasms - metabolism Stomach Neoplasms - pathology STUB1 Therapeutic applications Transcription Factors Tumor cell lines Tumorigenesis Tumors Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - metabolism Ubiquitination YAP-Signaling Proteins YAP1 Yes-associated protein China YAP1 chemoresistance STUB1 gastric cancer ubiquitination
ISSN:	1347-9032, 1349-7006, 1349-7006
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Abstract	Yes‐associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48‐linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions. Our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.
AbstractList	Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48-linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48-linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions. Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48-linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions. Yes‐associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48‐linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions. Our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.
Author	Tang, Dong‐E Xu, Yong Jiang, Hao‐Wu Lin, Lie‐Wen Liu, Dong‐Zhou Hong, Xiao‐Ping Dai, Yong Xu, Song‐Hui
AuthorAffiliation	1 Department of Clinical Medical Research Center The Second Clinical Medical College of Jinan University The First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's Hospital Shenzhen China 3 Department of Biochemistry, Marlene and Stewart Greenebaum Cancer Center University of Maryland School of Medicine Baltimore MD USA 2 Department of Anesthesiology and Center for the Study of Itch Washington University School of Medicine St. Louis MO USA
AuthorAffiliation_xml	– name: 1 Department of Clinical Medical Research Center The Second Clinical Medical College of Jinan University The First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's Hospital Shenzhen China – name: 2 Department of Anesthesiology and Center for the Study of Itch Washington University School of Medicine St. Louis MO USA – name: 3 Department of Biochemistry, Marlene and Stewart Greenebaum Cancer Center University of Maryland School of Medicine Baltimore MD USA
Author_xml	– sequence: 1 givenname: Dong‐E surname: Tang fullname: Tang, Dong‐E organization: The First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's Hospital – sequence: 2 givenname: Yong surname: Dai fullname: Dai, Yong organization: The First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's Hospital – sequence: 3 givenname: Lie‐Wen surname: Lin fullname: Lin, Lie‐Wen organization: The First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's Hospital – sequence: 4 givenname: Yong surname: Xu fullname: Xu, Yong organization: The First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's Hospital – sequence: 5 givenname: Dong‐Zhou surname: Liu fullname: Liu, Dong‐Zhou organization: The First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's Hospital – sequence: 6 givenname: Xiao‐Ping surname: Hong fullname: Hong, Xiao‐Ping organization: The First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's Hospital – sequence: 7 givenname: Hao‐Wu surname: Jiang fullname: Jiang, Hao‐Wu organization: Washington University School of Medicine – sequence: 8 givenname: Song‐Hui orcidid: 0000-0003-0269-9129 surname: Xu fullname: Xu, Song‐Hui email: songhuixu007@gmail.com organization: University of Maryland School of Medicine
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Copyright	2019 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 2019. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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Keywords	YAP1 chemoresistance STUB1 gastric cancer ubiquitination
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Snippet	Yes‐associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size,... Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size,...
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SubjectTerms	Adaptor Proteins, Signal Transducing - chemistry Adaptor Proteins, Signal Transducing - metabolism Animals Carcinogenesis Cell growth Cell Line, Tumor Cell Proliferation Cell survival Chemoresistance Drug Resistance, Neoplasm Female Gastric cancer Gene Expression Regulation, Neoplastic HEK293 Cells Humans Kinases Lysine - metabolism Mass spectrometry Medical prognosis Mice Mutation Neoplasm Transplantation Original Peptides Phosphoproteins - chemistry Phosphoproteins - metabolism Plasmids Protein Stability Proteins Proteolysis Scientific imaging Signal Transduction Statistical analysis Stomach Neoplasms - drug therapy Stomach Neoplasms - metabolism Stomach Neoplasms - pathology STUB1 Therapeutic applications Transcription Factors Tumor cell lines Tumorigenesis Tumors Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - metabolism Ubiquitination YAP-Signaling Proteins YAP1 Yes-associated protein
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Title	STUB1 suppresseses tumorigenesis and chemoresistance through antagonizing YAP1 signaling
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