Editors' ChoiceCancer

Without merlin, YAP drives RAS

Sci. Signal.  17 Nov 2015:
Vol. 8, Issue 403, pp. ec340
DOI: 10.1126/scisignal.aad8476

Neurofibromatosis type 2 is an autosomal-dominant tumor susceptibility syndrome caused by heterozygous mutations of NF2, which encodes merlin. In response to cell-cell contact, merlin activates the Hippo pathway, which suppresses the activity of the oncogenic transcription factor YAP and its cofactor TEAD. Activating mutations in the guanosine triphosphatase (GTPase) RAS and increased activity of downstream signaling through the mitogen-activated kinase (MAPK) pathway is common in various cancers. Garcia-Rendueles et al. found that loss of NF2 promotes the expression of mutant RAS in some thyroid cancers by enabling the transcriptional activity of YAP. Bioinformatics analysis of patient tumor tissue revealed that several types of RAS-mutant thyroid cancers also exhibit loss of heterozygosity in the chromosomal region containing the NF2 locus. Manipulating merlin abundance in RAS-mutant, NF2-wild-type or NF2-null thyroid cancer cells using RNA interference or transfection with wild-type or mutant forms of merlin revealed that merlin suppressed the expression of all isoforms of RAS and promoted the phosphorylation and cytoplasmic sequestration of YAP. Manipulation of YAP abundance revealed that YAP promoted the expression of mutant and wild-type RAS. In silico analysis predicted TEAD-binding sites in the promoters of the three RAS genes, and increasing merlin abundance or pharmacologically inhibiting YAP decreased the amount of YAP and TEAD1 at these sites. Knocking down YAP decreased RAS expression, MAPK signaling, and proliferation in RAS-mutant, NF2-null thyroid cancer cells. The findings suggest that targeting YAP may be therapeutically beneficial in RAS-mutant cancers, especially those lacking NF2.

M. E. R. Garcia-REndueles, J. C. Ricarte-Filho, B. R. Untch, I. Landa, J. A. Knauf, F. Voza, V. E. Smith, I. Ganly, B. S. Taylor, Y. Persaud, G. Oler, Y. Fang, S. C. Jhanwar, A. Viale, A. Heguy, K. H. Huberman, F. Giancotti, R. Ghossein, J. A. Fagin, NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition. Cancer Discov. 5, 1178–1193 (2015). [PubMed]

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