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Abstract
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. Here, we report 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.
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1 National Tsing-Hua University, Institute of Molecular and Cellular Biology and Department of Life Science, Hsinchu, Taiwan (GRID:grid.38348.34) (ISNI:0000 0004 0532 0580)
2 Chang Gung Memorial Hospital, Department of Surgery, Taoyuan, Taiwan (GRID:grid.413801.f) (ISNI:0000 0001 0711 0593)
3 Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan (GRID:grid.59784.37) (ISNI:0000000406229172)
4 University of California, Davis, Department of Biochemistry and Molecular Medicine, Sacramento, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684); Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan (GRID:grid.59784.37) (ISNI:0000000406229172)
5 University of California, San Diego, Institute of Engineering in Medicine, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)