Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP

Fa-Xing Yu; Jing Luo; Jung-Soon Mo; Guangbo Liu; Young Chul Kim; Zhipeng Meng; Ling Zhao; Gholam Peyman; Hong Ouyang; Wei Jiang; Jiagang Zhao; Xu Chen; Liangfang Zhang; Cun-Yu Wang; Boris C Bastian; Kang Zhang; Kun-Liang Guan

doi:10.1016/j.ccr.2014.04.017

Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP

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

Authors

Fa-Xing Yu¹, Jing Luo², Jung-Soon Mo¹, Guangbo Liu¹, Young Chul Kim¹, Zhipeng Meng¹, Ling Zhao³, Gholam Peyman⁴, Hong Ouyang⁵, Wei Jiang⁶, Jiagang Zhao⁵, Xu Chen⁷, Liangfang Zhang⁸, Cun-Yu Wang⁹, Boris C Bastian⁷, Kang Zhang¹⁰, Kun-Liang Guan¹¹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Animals
Cell Cycle Proteins
Cell Growth Processes / genetics
Cell Line, Tumor
Disease Models, Animal
Down-Regulation
GTP-Binding Protein alpha Subunits, Gq-G11 / genetics*
GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
HEK293 Cells
Humans
Male
Melanoma / genetics*
Melanoma / metabolism
Melanoma / pathology
Mice
Mice, Nude
Mice, SCID
Mutation*
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Phosphoproteins / genetics*
Phosphoproteins / metabolism
Signal Transduction
Transcription Factors / genetics*
Transcription Factors / metabolism
Transfection
Uveal Neoplasms / genetics*
Uveal Neoplasms / metabolism
Uveal Neoplasms / pathology
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Nuclear Proteins
Phosphoproteins
Transcription Factors
YAP-Signaling Proteins
YY1AP1 protein, human
Yap1 protein, mouse
GTP-Binding Protein alpha Subunits, Gq-G11

Supplementary concepts

Uveal melanoma

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding