Aberrant JMJD3 Expression Upregulates Slug to Promote Migration, Invasion, and Stem Cell–Like Behaviors in Hepatocellular Carcinoma

Abstract The Jumonji domain–containing chromatin remodeling factor JMJD3 has important roles in development and cancer. Here, we report a pivotal role for JMJD3 in sustaining the phenotype of aggressive hepatocellular carcinomas. Expression levels of JMJD3 in clinical specimens of hepatocellular carcinoma correlated inversely with patient survival. In hepatocellular carcinoma cells, we found that enforcing its overexpression induced epithelial–mesenchymal transition (EMT), invasive migration, stem cell–like traits, and metastatic properties. Conversely, silencing JMJD3 in hepatocellular carcinoma cells overexpressing it inhibited these aggressive phenotypes. Mechanistically, JMJD3 modulated H3K27me3 in the SLUG gene promoter, a histone mark associated with active SLUG transcription. SLUG silencing blocked JMJD3-induced EMT, stemness, and metastasis. Furthermore, SLUG expression in hepatocellular carcinoma clinical specimens correlated positively with JMJD3 expression. Our results establish JMJD3 as a critical driver of hepatocellular carcinoma stem cell–like and metastatic behaviors, with implications for prognosis and treatment. Cancer Res; 76(22); 6520–32. ©2016 AACR.