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

Meng Chen Wu; Hsin Hung Cheng; Ta Sen Yeh; Yi Chen Li; Tsan Jan Chen; Wei Yang Sit; Chih Pin Chuu; Hsing Jien Kung; Shu Chien; Wen Ching Wang

doi:10.1038/s41419-019-1305-y

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

Meng Chen Wu, Hsin Hung Cheng, Ta Sen Yeh, Yi Chen Li, Tsan Jan Chen, Wei Yang Sit, Chih Pin Chuu, Hsing Jien Kung, Shu Chien, Wen Ching Wang^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

26 Scopus citations

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.

Original language	English
Article number	68
Journal	Cell Death and Disease
Volume	10
Issue number	2
DOIs	https://doi.org/10.1038/s41419-019-1305-y
State	Published - 01 02 2019
Externally published	Yes

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Publisher Copyright:
© 2019, The Author(s).

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title = "KDM4B is a coactivator of c-Jun and involved in gastric carcinogenesis",

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.",

author = "Wu, {Meng Chen} and Cheng, {Hsin Hung} and Yeh, {Ta Sen} and Li, {Yi Chen} and Chen, {Tsan Jan} and Sit, {Wei Yang} and Chuu, {Chih Pin} and Kung, {Hsing Jien} and Shu Chien and Wang, {Wen Ching}",

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year = "2019",

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doi = "10.1038/s41419-019-1305-y",

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AU - Wu, Meng Chen

AU - Cheng, Hsin Hung

AU - Yeh, Ta Sen

AU - Li, Yi Chen

AU - Chen, Tsan Jan

AU - Sit, Wei Yang

AU - Chuu, Chih Pin

AU - Kung, Hsing Jien

AU - Chien, Shu

AU - Wang, Wen Ching

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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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SN - 2041-4889

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ER -

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

Abstract

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