JMJD2B Promotes Epithelial–Mesenchymal Transition by Cooperating with β-Catenin and Enhances Gastric Cancer Metastasis

Abstract

Purpose: This study investigated the role of histone demethylase Jumonji domain–containing protein 2B (JMJD2B) in promoting epithelial–mesenchymal transition (EMT) and underlying molecular mechanisms in the progression of gastric cancer. Experimental Design: The induction of EMT by JMJD2B in gastric cancer cells and its underlying mechanisms were examined by a series of assays. In vivo and in vitro assays were performed to clarify invasive potential of JMJD2B in gastric cancer cells. The expression dynamics of JMJD2B were detected using immunohistochemistry in 101 cases of primary gastric cancer tissues. Results: Inhibition of JMJD2B by specific siRNA suppresses EMT of gastric cancer cells, whereas ectopic expression of JMJD2B induces EMT. Importantly, JMJD2B is physically associated with β-catenin and enhances its nuclear localization and transcriptional activity. JMJD2B, together with β-catenin, binds to the promoter of the β-catenin target gene vimentin to increase its transcription by inducing H3K9 demethylation locally. JMJD2B inhibition attenuates migration and invasion of gastric cancer cells in vitro and metastasis in vivo. The expression of JMJD2B was positively correlated with tumor size (P = 0.017), differentiation status (P = 0.002), tumor invasion (P = 0.045), lymph node metastasis (P = 0.000), distant metastasis (P = 0.024), and tumor–node–metastasis (TNM) stage (P = 0.002) in patients with gastric cancer. Conclusions: The data reveal a novel function of JMJD2B in promoting EMT and gastric cancer invasion and metastasis, implicating JMJD2B as a potential target for reversing EMT and intervention of the progression of gastric cancer. Clin Cancer Res; 19(23); 6419–29. ©2013 AACR.