CADPE suppresses cyclin D1 expression in hepatocellular carcinoma by blocking IL-6-induced STAT3 activation.

The initiation and growth of hepatocellular carcinoma (HCC) are closely linked to chronic inflammation. Not only is cyclin D1 overexpressed, but it is also related to aggressive progression in HCC. However, the mechanism of expression cyclin D1, a cell-cycle regulator of paramount importance, in the tumor microenvironment remains unknown. Here, we investigated the mechanism of cyclin D1 expression induced by interleukin-6 (IL-6) and whether 3-[3,4-dihydroxy-phenyl]-acrylic acid 2-[3,4-dihydroxy-phenyl]-ethyl ester (CADPE), a derivate of caffeic acid, suppresses cyclin D1 expression. CADPE significantly inhibited IL-6-induced signal transducer and activator of transcription 3 (STAT3) activity in the Huh7 HCC cell line and attenuated IL-6-induced cyclin D1 transcription. Moreover, overexpression of constitutively active STAT3 increased cyclin D1 transcriptional activity and protein expression, whereas overexpression of a dominant-negative STAT3 deletion mutant (STAT3 (1-588)) reduced cyclin D1 transcriptional activity. In addition, CADPE effectively deacetylated histone 4 and prevented STAT3 recruitment to the cyclin D1 promoter, consistent with a role for the CADPE target, STAT3, in the regulation of cyclin D1 transcription. Collectively, these results indicate that CADPE suppresses cyclin D1 expression in HCC cells by blocking both IL-6-mediated STAT3 activation and recruitment of STAT3 to the cyclin D1 promoter.