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.
Highlights
Histone lysine demethylase 4 (KDM4), which catalyzes the removal of methyl-lysine marks from histone 3, includes four members, KDM4A, KDM4B, KDM4C, and KDM4D1
We demonstrate that KDM4B is a coactivator of c-Jun to regulate the expressions of IL-8, MMP1, and integrin αV
Of KDM4-knockdown lines, a significantly reduced signal of IL-8 was detected for two KDM4B-knockdown lines, but not for KDM4A- or KDM4C-knockdown lines without H. pylori infection (Fig. 1b, p < 0.01)
Summary
Histone lysine demethylase 4 (KDM4), which catalyzes the removal of methyl-lysine marks from histone 3, includes four members, KDM4A, KDM4B, KDM4C, and KDM4D1. Accumulating evidence implicates the overexpressions of KDM4A, KDM4B, and KDM4C in the efficient growth of human malignancies, including breast, colorectal, lung, prostate, and other tumors[1]. KDM4A and KDM4B are often amplified in gastric cancer, neuroblastoma, and ovarian cancer[8,9,10,11]. KDM4A regulates chromatin during DNA replication and stem cell genome reprogramming[8,12]. KDM4A can interact with the act as coactivators of androgen receptor and estrogen receptor, which are promising epigenetic drug targets[5,20,21,22,23]
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