title: Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway.
abstract: Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus and the culprit behind the human disease Kaposi sarcoma (KS), an AIDS-defining malignancy. KSHV encodes a viral G-protein-coupled receptor (vGPCR) critical for the initiation and progression of KS. In this study, we identified that YAP/TAZ, two homologous oncoproteins inhibited by the Hippo tumor suppressor pathway, are activated in KSHV-infected cells in vitro, KS-like mouse tumors and clinical human KS specimens. The KSHV-encoded vGPCR acts through Gq/11 and G12/13 to inhibit the Hippo pathway kinases Lats1/2, promoting the activation of YAP/TAZ. Furthermore, depletion of YAP/TAZ blocks vGPCR-induced cell proliferation and tumorigenesis in a xenograft mouse model. The vGPCR-transformed cells are sensitive to pharmacologic inhibition of YAP. Our study establishes a pivotal role of the Hippo pathway in mediating the oncogenic activity of KSHV and development of KS, and also suggests a potential of using YAP inhibitors for KS intervention.
authors.affiliation: 1] School of Life Sciences, Shandong University, Jinan, China [2] Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: F-X
authors.initials: FX
authors.lastname: Yu
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Y C
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Microbiology and Immunology and Viral Oncology Program, Miami Center for AIDS Research, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Naipauer
authors.affiliation: Department of Medicine, VA San Diego Healthcare System, The University of California, San Diego, La Jolla, CA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Looney
authors.affiliation: School of Life Sciences, Shandong University, Jinan, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Gutkind
authors.affiliation: Department of Microbiology and Immunology and Viral Oncology Program, Miami Center for AIDS Research, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Mesri
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: K-L
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000217:Acyltransferases; D000818:Animals; D018797:Cell Cycle Proteins; D002472:Cell Transformation, Viral / Q000235:genetics*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D017346:Protein Serine-Threonine Kinases