Abstract
<div>Abstract<p><b>Purpose:</b> Recent evidence indicates that a tumor suppressor gene <i>CEBPD</i> (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 <i>CEBPD</i> 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.</p><p><b>Experimental Design:</b> Methylation-specific PCR assay, reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed to dissect the signaling pathway of HMDB-induced <i>CEBPD</i> 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, <i>PPARG2</i> and <i>GADD153</i>. Finally, the anticancer effect of HMDB was examined in xenograft mice.</p><p><b>Results:</b> We demonstrate that CEBPD plays an essential role in HMDB-mediated apoptosis of cancer cells. HMDB up-regulates <i>CEBPD</i> transcription through the p38/CREB pathway, thus leading to transcriptional activation of <i>PPARG2</i> and <i>GADD153</i>. 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.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 16(23); 5770–80. ©2010 AACR.</i></p></div>
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