Research Interests
Cancer epigenetics
Epigenetic regulation in part involves a dynamic, reversible post-translational modification of histones, which convey inherited information concerning chromatin structure, and dictate the gene expression pattern. Methylation of histone tails has been recently recognized as a key post-translational modification in epigenetics owing to the discovery of histone demethylases. Misregulated methylated status of histones from mutational inactivation or abnormal expression of these modifiers has been implicated in oncogenesis.
KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A–D) constitute an important class of epigenetic modulators in the transcriptional activation of cellular processes and genome stability. Interleukin-8 (IL-8) is overexpressed in gastric cancer, but the mechanisms and particularly the role of the epigenetic regulation of IL-8, are unclear. In our recent study, we show that KDM4B, but not KDM4A/4C, upregulated IL-8 production in the absence or presence of Helicobacter pylori. Moreover, KDM4B physically interacts with c-Jun on IL-8, MMP1, and ITGAV promoters via its demethylation activity. The depletion of KDM4B leads to the decreased expression of integrin αV, which is exploited by H. pylori carrying the type IV secretion system, reducing IL-8 production and cell migration. Elevated KDM4B expression is significantly associated with the abundance of p-c-Jun in gastric cancer and is linked to a poor clinical outcome. Together, our results suggest that KDM4B is a key regulator of JNK/c-Jun-induced processes and is a valuable therapeutic target.
Figure Illustration: A schematic diagram shows that the histone demethylase KDM4B participates in gastric carcinogenesis via its interaction with the AP-1 transcriptional factor c-Jun. The c-Jun-KDM4B complex contributes to tumorigenesis through upregulation of IL-8, MMP1 and ITGAV, which is even more pronounced by challenge with H. pylori. Silencing of KDM4B represents a new strategy to suppress the c-Jun/IL-8 pathway.