H3K27 Demethylase JMJD3 Employs the NF-κB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote Melanoma Progression and Metastasis

American Association for Cancer Research (AACR) - Tập 76 Số 1 - Trang 161-170 - 2016
Woo‐Yong Park1, Beom-Jin Hong1, Jungsul Lee2, Chulhee Choi2,3, Mi‐Young Kim1,3
11Department of Biological Sciences, Cancer Metastasis Control Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
22Department of Bio and Brain Engineering, Cancer Metastasis Control Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
33KAIST Institute for the BioCentury, Cancer Metastasis Control Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

Tóm tắt

Abstract Histone methylation is a key epigenetic mark that regulates gene expression. Recently, aberrant histone methylation patterns caused by deregulated histone demethylases have been associated with carcinogenesis. However, the role of histone demethylases, particularly the histone H3 lysine 27 (H3K27) demethylase JMJD3, remains largely uncharacterized in melanoma. Here, we used human melanoma cell lines and a mouse xenograft model to demonstrate a requirement for JMJD3 in melanoma growth and metastasis. Notably, in contrast with previous reports examining T-cell acute lymphoblastic leukemia and hepatoma cells, JMJD3 did not alter the general proliferation rate of melanoma cells in vitro. However, JMJD3 conferred melanoma cells with several malignant features such as enhanced clonogenicity, self-renewal, and transendothelial migration. In addition, JMJD3 enabled melanoma cells not only to create a favorable tumor microenvironment by promoting angiogenesis and macrophage recruitment, but also to activate protumorigenic PI3K signaling upon interaction with stromal components. Mechanistic investigations demonstrated that JMJD3 transcriptionally upregulated several targets of NF-κB and BMP signaling, including stanniocalcin 1 (STC1) and chemokine (C–C motif) ligand 2 (CCL2), which functioned as downstream effectors of JMJD3 in self-renewal and macrophage recruitment, respectively. Furthermore, JMJD3 expression was elevated and positively correlated with that of STC1 and CCL2 in human malignant melanoma. Moreover, we found that BMP4, another JMJD3 target gene, regulated JMJD3 expression via a positive feedback mechanism. Our findings reveal a novel epigenetic mechanism by which JMJD3 promotes melanoma progression and metastasis, and suggest JMJD3 as a potential target for melanoma treatment. Cancer Res; 76(1); 161–70. ©2016 AACR.

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American Association for Cancer Research (AACR)

Tập 76 Số 1

161-170

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