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

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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5770-5780
Number of pages11
JournalClinical Cancer Research
Volume16
Issue number23
DOIs
Publication statusPublished - Dec 1 2010
Externally publishedYes

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CCAAT-Enhancer-Binding Protein-delta
Retinoblastoma
Apoptosis
Genes
Neoplasms
Heterografts
SCID Mice
Chromatin Immunoprecipitation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells. / Pan, Yen Chun; Li, Chien Feng; Ko, Chiung Yuan; Pan, Min Hsiung; Chen, Pei Jung; Tseng, Joseph T.; Wu, Wen Chun; Chang, Wen Chang; Huang, A. Mei; Sterneck, Esta; Wang, Ju Ming.

In: Clinical Cancer Research, Vol. 16, No. 23, 01.12.2010, p. 5770-5780.

Research output: Contribution to journalArticle

Pan, YC, Li, CF, Ko, CY, Pan, MH, Chen, PJ, Tseng, JT, Wu, WC, Chang, WC, Huang, AM, Sterneck, E & Wang, JM 2010, 'CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells', Clinical Cancer Research, vol. 16, no. 23, pp. 5770-5780. https://doi.org/10.1158/1078-0432.CCR-10-1025
Pan, Yen Chun ; Li, Chien Feng ; Ko, Chiung Yuan ; Pan, Min Hsiung ; Chen, Pei Jung ; Tseng, Joseph T. ; Wu, Wen Chun ; Chang, Wen Chang ; Huang, A. Mei ; Sterneck, Esta ; Wang, Ju Ming. / CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 23. pp. 5770-5780.
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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.",
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AU - Pan, Yen Chun

AU - Li, Chien Feng

AU - Ko, Chiung Yuan

AU - Pan, Min Hsiung

AU - Chen, Pei Jung

AU - Tseng, Joseph T.

AU - Wu, Wen Chun

AU - Chang, Wen Chang

AU - Huang, A. Mei

AU - Sterneck, Esta

AU - Wang, Ju Ming

PY - 2010/12/1

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N2 - 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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