C/EBPδ expression in a BCR-ABL-positive cell line induces growth arrest and myeloid differentiation

Gery, Sigal; Tanosaki, Sakae; Hofmann, Werner; Koppel, Ahrin; Koeffler, H. Phillip

doi:10.1038/sj.onc.1208393

Cited by 59 publications

(73 citation statements)

References 41 publications

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“…Previous studies have also suggested that CEBPD plays a vital role in inflammation and inflammatory disease processes (12,13). However, unlike the inflammatory effectors NF-kB and STAT3 that are consistently activated in cancer cells, CEBPD inactivation has been observed in several types of cancer, including cervical and hepatocellular carcinoma (10,14), breast (15), prostate cancer (9), and leukemia (16). In addition to acting as a tumor suppressor, several recent reports have suggested that CEBPD plays an oncogenic role under certain conditions (17,18).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Wang

Chu

et al. 2017

Clinical Cancer Research

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Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy.Experimental Design: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity.Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel.Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201.

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Section: Introductionmentioning

confidence: 99%

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Wang

Chu

et al. 2017

Clinical Cancer Research

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“…In addition, it has been suggested that CEBPD can potentially mediate differentiation because it can respond to all-transretinoic acid (RA) and vitamin D3 treatment (8). Thus, verifying the effects of CEBPD induction in cancer cells could be interesting because CEBPD might be an important target for the development of chemotherapeutic agents.…”

mentioning

confidence: 99%

“…cells (7,8). CEBPD is also involved in regulating proapoptotic gene expression during mammary gland involution (9).…”

mentioning

confidence: 99%

CEBPD Reverses RB/E2F1-Mediated Gene Repression and Participates in HMDB-Induced Apoptosis of Cancer Cells

Pan

et al. 2010

Clinical Cancer Research

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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. Clin Cancer Res; 16(23); 5770-80. Ó2010 AACR.

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“…In vitro, C/EBPδ inhibits the growth of tumor cell lines, is associated with G 0 growth arrest, or induces differentiation (6)(7)(8), and promotes genomic stability of mouse embryo fibroblasts (MEFs) (9). C/EBPδ expression correlates with low proliferation and histological grade in meningiomas (10) and was in a 70-gene signature predicting better survival of breast cancer patients (11).…”

mentioning

confidence: 99%

C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

Pawar

Sarkar

Balamurugan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor CCAAT/enhancer binding protein δ (C/EBPδ, CEBPD, NFIL-6β) has tumor suppressor function; however, the molecular mechanism(s) by which C/EBPδ exerts its effect are largely unknown. Here, we report that C/EBPδ induces expression of the Cdc27 (APC3) subunit of the anaphase promoting complex/cyclosome (APC/C), which results in the polyubiquitination and degradation of the prooncogenic cell cycle regulator cyclin D1, and also down-regulates cyclin B1, Skp2, and Plk-1. In C/EBPδ knockout mouse embryo fibroblasts (MEF) Cdc27 levels were reduced, whereas cyclin D1 levels were increased even in the presence of activated GSK-3β. Silencing of C/EBPδ, Cdc27, or the APC/C coactivator Cdh1 (FZR1) in MCF-10A breast epithelial cells increased cyclin D1 protein expression. Like C/EBPδ, and in contrast to cyclin D1, Cdc27 was down-regulated in several breast cancer cell lines, suggesting that Cdc27 itself may be a tumor suppressor. Cyclin D1 is a known substrate of polyubiquitination complex SKP1/CUL1/F-box (SCF), and our studies show that Cdc27 directs cyclin D1 to alternative degradation by APC/C. These findings shed light on the role and regulation of APC/C, which is critical for most cellular processes.

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C/EBPδ expression in a BCR-ABL-positive cell line induces growth arrest and myeloid differentiation

Cited by 59 publications

References 41 publications

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

CEBPD Reverses RB/E2F1-Mediated Gene Repression and Participates in HMDB-Induced Apoptosis of Cancer Cells

C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

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