KDM4B is a coactivator of c-Jun and involved in gastric carcinogenesis

• Published in: Cell death & disease 2019-01, Vol.10 (2), p.68, Article 68
• Main Authors: Wu, Meng-Chen, Cheng, Hsin-Hung, Yeh, Ta-Sen, Li, Yi-Chen, Chen, Tsan-Jan, Sit, Wei Yang, Chuu, Chih-Pin, Kung, Hsing-Jien, Chien, Shu, Wang, Wen-Ching
• Format: Article
• Language: English
• Subjects: 13/106; 13/21; 13/51; 14/1; 14/63; 38/109; 38/61; 38/79; 38/89; 38/90; 631/337/176; 631/67/1504/1829; 631/80/86/2366; 82/80; Antibodies; Biochemistry; Biomedical and Life Sciences; c-Jun protein; Carcinogenesis; Carcinogenesis - metabolism; Cell adhesion & migration; Cell Biology; Cell Culture; Cell migration; Cell Movement - genetics; Demethylation; Epigenetics; Gastric cancer; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genomes; HEK293 Cells; Helicobacter pylori - metabolism; Humans; Immunology; Integrin alphaV - metabolism; Interleukin 8; Interleukin-8 - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Life Sciences; Lysine; MAP Kinase Signaling System; Matrix Metalloproteinase 1 - metabolism; Prognosis; Stomach Neoplasms - metabolism; Stomach Neoplasms - microbiology; Stomach Neoplasms - mortality; Stomach Neoplasms - pathology; Survival Rate; Therapeutic applications; Transcription activation; Transcription factors; Transcriptional Activation; Transfection
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1305-y

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.