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Cancer Cell. 2014 Jun 16;25(6):822-30. doi: 10.1016/j.ccr.2014.04.017. Epub 2014 May 29.

Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP.

Author information

1
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
2
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.
3
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.
4
Arizona Retinal Specialists, Sun City West, AZ 85375, USA.
5
Department of Ophthalmology and Shiley Eye Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
6
Molecular Medicine Research Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
7
Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
8
Department of Nanoengineering, University of California, San Diego, La Jolla, CA 92093, USA.
9
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, University of California, Los Angeles, School of Dentistry, Los Angeles, CA 90095, USA.
10
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.
11
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.

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.

PMID:
24882516
PMCID:
PMC4075337
DOI:
10.1016/j.ccr.2014.04.017
[Indexed for MEDLINE]
Free PMC Article
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