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.
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Acknowledgements
We thank AIDS and Cancer Specimen Resource at the University of California, San Francisco (particularly Ronald Honrada, Andrew Ma and Michael McGrath) for providing the tissue microarrays and carrying out the HHV-8 staining. We also thank Jenna Jewell, Steve Plouffe and Fabian Flores for critical reading of this manuscript, and Drs Dirk Dittmer, Carsten Gram Hansen and Toshiro Moroishi for insightful discussions. EAM and JN would like to thank Santas Rosario and Darlah Lopez Rodriguez for their help with the infection systems. This study was supported by grants from NIH/NCI P30 CA23100, NIAID P30 AI36214, R01CA132809, R01GM51586 (to KLG) and the Chinese Scholarship Council (to GL). EAM and JN were supported by NIH Grants CA136387 and Miami CFAR Grant P30AI073961.
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Liu, G., Yu, FX., Kim, Y. et al. Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway. Oncogene 34, 3536–3546 (2015). https://doi.org/10.1038/onc.2014.281
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DOI: https://doi.org/10.1038/onc.2014.281
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