Widespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells.
Tumor invasion and metastasis involves complex remodeling of gene expression programs governing epithelial homeostasis. Mutational activation of the RAS-ERK is a frequent occurrence in many cancers and has been shown to drive overexpression of the AP-1 family transcription factor FRA1, a potent regu...
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oai:doaj.org-article:d7fe9ee98a4f408bb231db36ea198d142021-11-18T08:26:40ZWidespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells.1932-620310.1371/journal.pone.0088950https://doaj.org/article/d7fe9ee98a4f408bb231db36ea198d142014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24658684/?tool=EBIhttps://doaj.org/toc/1932-6203Tumor invasion and metastasis involves complex remodeling of gene expression programs governing epithelial homeostasis. Mutational activation of the RAS-ERK is a frequent occurrence in many cancers and has been shown to drive overexpression of the AP-1 family transcription factor FRA1, a potent regulator of migration and invasion in a variety of tumor cell types. However, the nature of FRA1 transcriptional targets and the molecular pathways through which they promote tumor progression remain poorly understood. We found that FRA1 was strongly expressed in tumor cells at the invasive front of human colorectal cancers (CRCs), and that its depletion suppressed mesenchymal-like features in CRC cells in vitro. Genome-wide analysis of FRA1 chromatin occupancy and transcriptional regulation identified epithelial-mesenchymal transition (EMT)-related genes as a major class of direct FRA1 targets in CRC cells. Expression of the pro-mesenchymal subset of these genes predicted adverse outcomes in CRC patients, and involved FRA-1-dependent regulation and cooperation with TGFβ signaling pathway. Our findings reveal an unexpectedly widespread and direct role for FRA1 in control of epithelial-mesenchymal plasticity in CRC cells, and suggest that FRA1 plays an important role in mediating cross talk between oncogenic RAS-ERK and TGFβ signaling networks during tumor progression.Jeannine DieschElaine SanijOmer GilanChristopher LoveHoanh TranNicholas I FlemingJason EllulMarcia AmaliaIzhak HavivRichard B PearsonEugene TulchinskyJohn M MariadasonOliver M SieberRoss D HannanAmardeep S DhillonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e88950 (2014) |
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DOAJ |
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DOAJ |
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| topic |
Medicine R Science Q |
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Medicine R Science Q Jeannine Diesch Elaine Sanij Omer Gilan Christopher Love Hoanh Tran Nicholas I Fleming Jason Ellul Marcia Amalia Izhak Haviv Richard B Pearson Eugene Tulchinsky John M Mariadason Oliver M Sieber Ross D Hannan Amardeep S Dhillon Widespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells. |
| description |
Tumor invasion and metastasis involves complex remodeling of gene expression programs governing epithelial homeostasis. Mutational activation of the RAS-ERK is a frequent occurrence in many cancers and has been shown to drive overexpression of the AP-1 family transcription factor FRA1, a potent regulator of migration and invasion in a variety of tumor cell types. However, the nature of FRA1 transcriptional targets and the molecular pathways through which they promote tumor progression remain poorly understood. We found that FRA1 was strongly expressed in tumor cells at the invasive front of human colorectal cancers (CRCs), and that its depletion suppressed mesenchymal-like features in CRC cells in vitro. Genome-wide analysis of FRA1 chromatin occupancy and transcriptional regulation identified epithelial-mesenchymal transition (EMT)-related genes as a major class of direct FRA1 targets in CRC cells. Expression of the pro-mesenchymal subset of these genes predicted adverse outcomes in CRC patients, and involved FRA-1-dependent regulation and cooperation with TGFβ signaling pathway. Our findings reveal an unexpectedly widespread and direct role for FRA1 in control of epithelial-mesenchymal plasticity in CRC cells, and suggest that FRA1 plays an important role in mediating cross talk between oncogenic RAS-ERK and TGFβ signaling networks during tumor progression. |
| format |
article |
| author |
Jeannine Diesch Elaine Sanij Omer Gilan Christopher Love Hoanh Tran Nicholas I Fleming Jason Ellul Marcia Amalia Izhak Haviv Richard B Pearson Eugene Tulchinsky John M Mariadason Oliver M Sieber Ross D Hannan Amardeep S Dhillon |
| author_facet |
Jeannine Diesch Elaine Sanij Omer Gilan Christopher Love Hoanh Tran Nicholas I Fleming Jason Ellul Marcia Amalia Izhak Haviv Richard B Pearson Eugene Tulchinsky John M Mariadason Oliver M Sieber Ross D Hannan Amardeep S Dhillon |
| author_sort |
Jeannine Diesch |
| title |
Widespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells. |
| title_short |
Widespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells. |
| title_full |
Widespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells. |
| title_fullStr |
Widespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells. |
| title_full_unstemmed |
Widespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells. |
| title_sort |
widespread fra1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/d7fe9ee98a4f408bb231db36ea198d14 |
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