Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis Journal Article
| Authors: | Eisinger-Mathason, T. S. K.; Mucaj, V.; Biju, K. M.; Nakazawa, M. S.; Gohil, M.; Cash, T. P.; Yoon, S. S.; Skuli, N.; Park, K. M.; Gerecht, S.; Simon, M. C. |
| Article Title: | Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis |
| 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. © 2015, National Academy of Sciences. All rights reserved. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; protein expression; unclassified drug; human cell; promoter region; cancer growth; nonhuman; drug targeting; cell proliferation; animal cell; mouse; animal tissue; complex formation; reverse transcription polymerase chain reaction; tumor volume; protein protein interaction; animal experiment; animal model; protein; transcription factor; in vivo study; in vitro study; carcinogenesis; sarcoma; messenger rna; chromatin; quantitative analysis; soft tissue sarcoma; binding site; gene control; gene silencing; rhabdomyosarcoma; hippo; embryonal rhabdomyosarcoma; copy number variation; yap; hippo protein; transcription factor yap; g2 phase cell cycle checkpoint; human; priority journal; article; foxm1; tead1 protein; thiostrepton; transcription factor foxm1 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 112 |
| Issue: | 26 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2015-06-30 |
| Start Page: | E3402 |
| End Page: | E3411 |
| Language: | English |
| DOI: | 10.1073/pnas.1420005112 |
| PROVIDER: | scopus |
| PMCID: | PMC4491775 |
| PUBMED: | 26080399 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
