| EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor. | |
| | |
MedLine Citation:
|
PMID: 20514024 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Synovial sarcoma is a high-grade soft tissue malignancy, for which current cytotoxic chemotherapies provide limited benefit. Although histone deacetylase (HDAC) inhibitors are known to suppress synovial sarcoma in vitro and in vivo, the exact mechanism is not clear. In this study, we report a central role of the transcription factor, early growth response-1 (EGR1), in the regulation of HDAC inhibitor-induced apoptotic cell death in synovial sarcoma. The SS18-SSX oncoprotein, characteristic of synovial sarcoma, maintains EGR1 expression at low levels, whereas it is significantly increased after HDAC inhibitor treatment. On the contrary, EGR1 knockdown leads to a decrease in HDAC inhibitor-induced apoptosis. Moreover, we find that under these conditions phosphatase and tensin homolog deleted in chromosome 10 (PTEN) is upregulated and this occurs through direct binding of EGR1 to an element upstream of the PTEN promoter. Using a combination of gain- and loss-of-function approaches, we show that EGR1 modulation of PTEN contributes to HDAC inhibitor-induced apoptosis in synovial sarcoma. Finally, restoration of EGR1 or PTEN expression is sufficient to induce synovial sarcoma cell death. Taken together, our findings indicate that SS18-SSX-mediated attenuation of an EGR1-PTEN network regulates synovial sarcoma cell survival, and that HDAC inhibitor-mediated apoptosis operates at least in part through reactivation of this pathway. |
| | |
Authors:
|
L Su; H Cheng; A V Sampaio; T O Nielsen; T M Underhill |
Related Documents
:
|
17823284 - Molecular interactions between t cells and fibroblast-like synoviocytes: role of membra... 8333924 - Autoimmune recognition of cartilage collagens. 21213304 - Suppressed microglial e prostanoid receptor 1 signaling selectively reduces tumor necro... 16804834 - Future aspects of hemophilia research and care. 11839814 - Embryonic lethality caused by apoptosis during gastrulation in mice lacking the gene of... 23238614 - Synthetic response of stimulated respiratory epithelium: modulation by prednisolone and... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-31 |
Journal Detail:
|
Title: Oncogene Volume: 29 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2010 Jul |
Date Detail:
|
Created Date: 2010-07-29 Completed Date: 2010-08-20 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
|
Languages: eng Pagination: 4352-61 Citation Subset: IM |
Affiliation:
|
Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Apoptosis
/
drug effects* Cell Line, Tumor Early Growth Response Protein 1 / antagonists & inhibitors, physiology* Histone Deacetylase Inhibitors / pharmacology* Humans PTEN Phosphohydrolase / physiology* Sarcoma, Synovial / drug therapy*, pathology |
| Chemical | |
Reg. No./Substance:
|
0/EGR1 protein, human; 0/Early Growth Response Protein 1; 0/Histone Deacetylase Inhibitors; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: miR-200bc/429 cluster targets PLCgamma1 and differentially regulates proliferation and EGF-driven in...
Next Document: Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human ca...