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

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 112; no. 26; pp. E3402 - E3411
Main Authors Eisinger-Mathason, T. S. Karin, Mucaj, Vera, Biju, Kevin M., Nakazawa, Michael S., Gohil, Mercy, Cash, Timothy P., Yoon, Sam S., Skuli, Nicolas, Park, Kyung Min, Gerecht, Sharon, Simon, M. Celeste
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 30.06.2015
National Acad Sciences
SeriesPNAS Plus
Subjects
Adaptor Proteins, Signal Transducing - metabolism
Biological Sciences
Carcinogenesis
Cell Line, Tumor
cell proliferation
Cell Proliferation - physiology
Deregulation
drug therapy
fibrosarcoma
Forkhead Box Protein M1
Forkhead Transcription Factors - metabolism
Forkhead Transcription Factors - physiology
Gene expression
Hippo Signaling Pathway
Human subjects
Humans
Patients
Phosphoproteins - metabolism
PNAS Plus
Protein Serine-Threonine Kinases - metabolism
resection
Sarcoma
Sarcoma - metabolism
Sarcoma - pathology
Tissues
Transcription Factors
Tumors
YAP-Signaling Proteins
YAP
sarcoma
FOXM1
Hippo
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Summary: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.
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1T.S.K.E.-M. and V.M. contributed equally to this work.
Edited by Joan S. Brugge, Harvard Medical School, Boston, MA, and approved May 18, 2015 (received for review October 18, 2014)
Author contributions: T.S.K.E.-M. and M.C.S. designed research; T.S.K.E.-M., V.M., K.M.B., M.S.N., M.G., T.P.C., and N.S. performed research; T.S.K.E.-M., M.G., S.S.Y., K.M.P., and S.G. contributed new reagents/analytic tools; T.S.K.E.-M. analyzed data; and T.S.K.E.-M., V.M., and M.C.S. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1420005112