23030

KDM4B

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 beta-catenin and enhances its nuclear localization and transcriptional activity. JMJD2B, together with beta-catenin, binds to the promoter of the beta-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.CI - (c)2013 AACR.

Lysine (K)-specific demethylase 4B (KDM4B) is a histone H3K9 demethylase and is reported to activate gene transcription through regulation of chromatin structures. Previous research has revealed that KDM4B plays special regulatory roles in colorectal, prostate and gastric cancers. However, its physiological role in pancreatic cancer remains largely unknown. In the present study, it is demonstrated KDM4B plays a crucial in epithelial-mesenchymal transition (EMT) in pancreatic cancer. siRNA mediated silencing of KDM4B inhibits cell migration, invasion and EMT. Moreover, KDM4B was demonstrated to epigenetically regulate the expression of ZEB1 in the TGF-beta-induced EMT process. In tumor tissues of pancreatic cancer patient, the protein level of KDM4B was positively correlated with ZEB1. In conclusion, our results suggested that KDM4B is a key mediator in EMT process, and may serve as an important prognostic marker and therapeutic target for the metastatic progression of human pancreatic cancer.CI - (c) The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.