NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition Journal Article


Authors: Garcia-Rendueles, M. E. R.; Ricarte-Filho, J. C.; Untch, B. R.; Landa, I.; Knauf, J. A.; Voza, F.; Smith, V. E.; Ganly, I.; Taylor, B. S.; Persaud, Y.; Oler, G.; Fang, Y.; Jhanwar, S. C.; Viale, A.; Heguy, A.; Huberman, K. H.; Giancotti, F.; Ghossein, R.; Fagin, J. A.
Article Title: NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition
Abstract: Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation is insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP–TEAD transcriptional program. We find that the three RAS genes are themselves YAP–TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacologic disruption of YAP–TEAD with verteporfin blocks RAS transcription and signaling and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS -mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability. SIGNIFICANCE: Intensifi cation of mutant RAS signaling through copy-number imbalances is commonly associated with transformation. We show that NF2 /merlin inactivation augments mutant RAS signaling by promoting YAP/TEAD-driven transcription of oncogenic and wild-type RAS, resulting in greater MAPK output and increased sensitivity to MEK inhibitors. © 2015 American Association for Cancer Research.
Keywords: immunohistochemistry; controlled study; human tissue; protein expression; unclassified drug; gene mutation; gene sequence; human cell; single nucleotide polymorphism; raf protein; nonhuman; mouse; actin; animal tissue; gene expression; protein depletion; animal experiment; animal model; gene frequency; transcription factor; oncogene h ras; fluorescence in situ hybridization; messenger rna; chromatin immunoprecipitation; echography; western blotting; transactivation; mitogen activated protein kinase 1; checkpoint kinase 2; ras protein; real time polymerase chain reaction; gene silencing; gene dosage; cyclin d1; doxycycline; k ras protein; chromosome loss; mitogen activated protein kinase kinase; merlin; p21 activated kinase; complementary dna; connective tissue growth factor; chromosome 22q; dna isolation; oncogene n ras; e1a associated p300 protein; colony formation; rna isolation; verteporfin; transcription factor yap; rac1 protein; crk like protein; poorly differentiated thyroid cancer; human; male; female; article; thyroid cancer cell line
Journal Title: Cancer Discovery
Volume: 5
Issue: 11
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2015-11-01
Start Page: 1178
End Page: 1193
Language: English
DOI: 10.1158/2159-8290.cd-15-0330
PROVIDER: scopus
PMCID: PMC4642441
PUBMED: 26359368
DOI/URL:
Notes: Export Date: 2 December 2015 -- Source: Scopus
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