Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

T. S.Karin Eisinger-Mathason, Vera Mucaj, Kevin M. Biju, Michael S. Nakazawa, Mercy Gohil, Timothy P. Cash, Sam S. Yoon, Nicolas Skuli, Kyung Min Park, Sharon Gerecht, M. Celeste Simon

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.

Original languageEnglish (US)
Pages (from-to)E3402-E3411
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number26
DOIs
StatePublished - Jun 30 2015
Externally publishedYes

Keywords

  • FOXM1
  • Hippo
  • Sarcoma
  • YAP

ASJC Scopus subject areas

  • General

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