| CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells. | |
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MedLine Citation:
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PMID: 20971808 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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PURPOSE: Recent evidence indicates that a tumor suppressor gene CEBPD (CCAAT/enhancer-binding protein delta) is downregulated in many cancers including cervical cancer, which provides a therapeutic potential associated with its reactivation. However, little is known for CEBPD activators and the effect of reactivation of CEBPD transcription upon anticancer drug treatment. In this study, we identified a novel CEBPD activator, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB). The purpose of this study is to characterize the mechanism of HMDB-induced CEBPD activation and its potential effect in cancer therapy. EXPERIMENTAL DESIGN: Methylation-specific PCR assay, reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed to dissect the signaling pathway of HMDB-induced CEBPD transcription. Furthermore, a consequence of HMDB-induced CEBPD expression was linked with E2F1 and retinoblastoma (RB), which discloses the scenario of CEBPD, E2F1, and RB bindings and transcriptional regulation on the promoters of proapoptotic genes, PPARG2 and GADD153. Finally, the anticancer effect of HMDB was examined in xenograft mice. RESULTS: We demonstrate that CEBPD plays an essential role in HMDB-mediated apoptosis of cancer cells. HMDB up-regulates CEBPD transcription through the p38/CREB pathway, thus leading to transcriptional activation of PPARG2 and GADD153. Furthermore, increased level of CEBPD attenuates E2F1-induced cancer cell proliferation and partially rescues RB/E2F1-mediated repression of PPARG2 and GADD153 transcription. Moreover, HMDB treatment attenuates the growth of A431 xenografts in severe combined immunodeficient mice mice. CONCLUSIONS: These results clearly demonstrate that HMDB kills cancer cells through activation of CEBPD pathways and suggest that HMDB can serve as a superior chemotherapeutic agent with limited potential for adverse side effects. |
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Authors:
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Yen-Chun Pan; Chien-Feng Li; Chiung-Yuan Ko; Min-Hsiung Pan; Pei-Jung Chen; Joseph T Tseng; Wen-Chun Wu; Wen-Chang Chang; A-Mei Huang; Esta Sterneck; Ju-Ming Wang |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-22 |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 16 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-08 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 5770-80 Citation Subset: IM |
Copyright Information:
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©2010 AACR. |
Affiliation:
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Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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