title: Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP.
abstract: Uveal melanoma (UM) is the most common cancer in adult eyes. Approximately 80% of UMs harbor somatic activating mutations in GNAQ or GNA11 (encoding Gq or G11, respectively). Herein, we show in both cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G protein-coupled receptor signaling. YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations. This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11.
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Fa-Xing
authors.initials: FX
authors.lastname: Yu
authors.affiliation: Department of Ophthalmology and Shiley Eye Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Ophthalmology of the Second Xiangya Hospital, International Academy of Translational Medicine, Central South University, Changsha 410011, China; Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jung-Soon
authors.initials: JS
authors.lastname: Mo
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Guangbo
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Ophthalmology and Shiley Eye Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Arizona Retinal Specialists, Sun City West, AZ 85375, USA.
authors.forename: Gholam
authors.initials: G
authors.lastname: Peyman
authors.affiliation: Department of Ophthalmology and Shiley Eye Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Ophthalmology and Shiley Eye Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jiagang
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Nanoengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, University of California, Los Angeles, School of Dentistry, Los Angeles, CA 90095, USA.
authors.forename: Cun-Yu
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.affiliation: Department of Ophthalmology and Shiley Eye Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Ophthalmology of the Second Xiangya Hospital, International Academy of Translational Medicine, Central South University, Changsha 410011, China; Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Veterans Administration Healthcare System, San Diego, CA 92161, USA. Electronic address: kang.zhang@gmail.com.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014604:Uveal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000091102:YAP-Signaling Proteins; D000098943:Uveal Melanoma
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C456659:YY1AP1 protein, human; C486223:Yap1 protein, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11