NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition.

Abstract

UNLABELLED:

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:

Intensification 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.

• Authors: Maria E R Garcia-Rendueles, Julio C Ricarte-Filho, Brian R Untch, Iňigo Landa, Jeffrey A Knauf, Francesca Voza, Vicki E Smith, Ian Ganly, Barry S Taylor, Yogindra Persaud, Gisele Oler, Yuqiang Fang, Suresh C Jhanwar, Agnes Viale, Adriana Heguy, Kety H Huberman, Filippo Giancotti, Ronald Ghossein, James A Fagin
• Journal: Cancer discovery (Cancer Discov) Vol. 5 Issue 11 Pg. 1178-93 (Nov 2015) ISSN: 2159-8290 [Electronic] United States
• PMID: 26359368 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Cell Cycle Proteins
• Neurofibromin 2
• Nuclear Proteins
• Protein Kinase Inhibitors
• Transcription Factors
• YY1AP1 protein, human
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Binding Sites
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• Chromosome Deletion
• Chromosomes, Human, Pair 22
• DNA Copy Number Variations
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Gene Deletion
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Order
• Gene Targeting
• Genes, ras
• Humans
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• Models, Biological
• Neoplasm Staging
• Neurofibromin 2 (genetics)
• Nuclear Proteins (metabolism)
• Nucleotide Motifs
• Position-Specific Scoring Matrices
• Promoter Regions, Genetic
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Thyroid Neoplasms (drug therapy, genetics, metabolism, pathology)
• Transcription Factors (metabolism)
• Transcriptional Activation