Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway

LIU, G; YU, F-X; KIM, Y C; MENG, Z; NAIPAUER, J; LOONEY, D J; LIU, X; GUTKIND, J S; MESRI, E A; GUAN, K-L

ONCOGENE

NATURE PUBLISHING GROUP

Año: 2014 vol. 34 p. 3536 - 3546

0950-9232

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 ofKS. In this study, we identified that YAP/TAZ, two homologous oncoproteins inhibited by the Hippo tumor suppressor pathway, areactivated in KSHV-infected cells in vitro, KS-like mouse tumors and clinical human KS specimens. The KSHV-encoded vGPCR actsthrough 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 vGPCRtransformedcells are sensitive to pharmacologic inhibition of YAP. Our study establishes a pivotal role of the Hippo pathway inmediating the oncogenic activity of KSHV and development of KS, and also suggests a potential of using YAP inhibitors for KSintervention.