Abstract
Endothelin receptor A (ETAR) promotes tumorigenesis by stimulating cell proliferation, migration, and survival. However, the mechanism of ETAR in promoting tumor growth is largely unknown. In this study, we demonstrate that ETAR stimulates colon cell proliferation, migration, and tumorigenesis through the activation of YAP/TAZ, two transcription coactivators of the Hippo tumor suppressor pathway. Endothelin-1 treatment induced YAP/TAZ dephosphorylation, nuclear accumulation, and transcriptional activation in multiple colon cancer cells. ETAR stimulation acted via downstream G-protein Gαq/11 and Rho GTPase to suppress the Hippo pathway, thus leading to YAP/TAZ activation, which was required for ETAR-induced tumorigenesis. Overall, these results indicate a critical role of the YAP/TAZ axis in ETAR signaling. Cancer Res; 77(9); 2413-23. ©2017 AACR.
©2017 American Association for Cancer Research.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Carcinogenesis / genetics*
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Cell Movement / genetics
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Cell Proliferation / genetics
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / pathology
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Endothelin-1 / administration & dosage
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Endothelin-1 / genetics
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GTP-Binding Protein alpha Subunits / genetics
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Gene Expression Regulation, Neoplastic
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HCT116 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics*
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Phosphoproteins / genetics*
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Receptor, Endothelin A / genetics*
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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YAP-Signaling Proteins
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rho GTP-Binding Proteins / genetics
Substances
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Adaptor Proteins, Signal Transducing
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Endothelin-1
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GTP-Binding Protein alpha Subunits
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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Receptor, Endothelin A
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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WWTR1 protein, human
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YAP-Signaling Proteins
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YAP1 protein, human
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rho GTP-Binding Proteins