Editors' ChoiceCancer

A New Therapeutic Target in Uveal Melanoma

Sci. Signal.  24 Jun 2014:
Vol. 7, Issue 331, pp. ec172
DOI: 10.1126/scisignal.2005622

Mutations in GNAQ or GNA11—genes encoding the heterotrimeric G protein α subunits Gαq or Gα11, respectively—may be initiating events in melanomas that arise in the iris, ciliary body, or choroid of the eye [called uveal melanomas (UM)]. The UM-associated mutations inactivate the protein’s guanine triphosphatase (GTPase) function, enabling constitutive signaling downstream of G protein–coupled receptor (GPCR) activation. GPCRs can promote or inhibit the Hippo pathway, which suppresses tumor formation by phosphorylating transcriptional regulator Yes-associated protein (YAP). Now two studies show that mutant Gαq or Gα11 promote UM tumorigenesis by activating YAP (see Field and Harbour). Yu et al. found that overexpression of mutant Gαq or Gα11 (Gαq/11) decreased the phosphorylation of cotransfected YAP, increased the abundance of endogenous TAZ (a transcriptional coactivator), and induced the nuclear localization of YAP and TAZ in human embryonic kidney 293A (HEK293A) cells compared with cells overexpressing wild-type Gαq/11. Low phosphorylation and nuclear localization of YAP were seen in UM cell lines or patient tumors with GNAQ or GNA11 mutations, whereas UM lines with wild-type Gαq/11 (but mutant BRAF) showed cytoplasmic localization and comparatively increased phosphorylation of YAP. Knocking down GNAQ in GNAQ-mutant UM cells increased YAP phosphorylation and decreased its nuclear localization and interaction with TEAD, another transcriptional coactivator, and prevented tumor growth after subcutaneous injection in mice. Knocking down YAP or TAZ prevented the malignant transformation of melanocytes induced by overexpression of mutant Gαq/11, suggesting that Gαq/11 may initiate UM through this family of transcription factors. Both studies found that YAP activity and cell proliferation in either Gαq/11-mutant UM cells or Gαq/11-expressing HEK293 cells were independent of Gαq signaling through phospholipase C β. Instead, Feng et al. found that the guanine nucleotide exchange factor Trio was critical for YAP activation by mutant Gαq/11. Knocking down Trio or downstream Rho GTPases or inhibiting actin polymerization decreased nuclear YAP localization and target gene expression in UM cells that had mutant GNAQ. Between both studies, knocking down YAP in Gαq/11-mutant UM cells reduced proliferation, migration, and colony growth and impaired subcutaneous xenograft formation in mice. Additionally, both studies showed that verteporfin, an inhibitor of the YAP-TEAD interaction, suppressed UM cell proliferation and viability in culture and abrogated the growth of orthotopic xenografts in mice. The findings suggest that mutant Gαq/11 activates YAP through Trio-RhoGTPase signaling and that inhibiting this pathway may have therapeutic potential for UM patients.

F.-X. Yu, J. Luo, J.-S. Mo, G. Liu, Y. C. Kim, Z. Meng, L. Zhao, G. Peyman, H. Ouyang, W. Jiang, J. Zhao, X. Chen, L. Zhang, C.-Y. Wang, B. C. Bastian, K. Zhang, K.-L. Guan, Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25, 822–830 (2014). [PubMed]

X. Feng, M. S. Degese, R. Iglesias-Bartolome, J. P. Vaque, A. A. Molinolo, M. Rodrigues, M. R. Zaidi, B. R. Ksander, G. Merlino, A. Sodhi, Q. Chen, J. S. Gutkind, Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a Trio-regulated Rho GTPase signaling circuitry. Cancer Cell 25, 831–845 (2014). [PubMed]

M. G. Field, J. W. Harbour, GANQ/11 mutations in uveal melanoma: Is YAP the key to targeted therapy? Cancer Cell 25, 714–715 (2014). [PubMed]

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