CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells.

Abstract

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 23 Pg. 5770-80 (Dec 01 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20971808 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione
• E2F1 Transcription Factor
• Ketones
• Retinoblastoma Protein
• CCAAT-Enhancer-Binding Protein-delta
• Propane

Topics

• Animals
• Apoptosis (drug effects, genetics)
• CCAAT-Enhancer-Binding Protein-delta (genetics, metabolism, physiology)
• Cells, Cultured
• Down-Regulation (genetics)
• E2F1 Transcription Factor (physiology)
• Female
• Gene Expression Regulation, Neoplastic
• Gene Silencing (physiology)
• HeLa Cells
• Humans
• Ketones (pharmacology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasms (genetics, pathology)
• Propane (analogs & derivatives, pharmacology)
• Retinoblastoma Protein (physiology)
• Xenograft Model Antitumor Assays