(The) opposing roles of JMJD3 and UTX, histone H3 Lys27 demethylases, in melanoma progression and metastasis

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 roles of histone demethylases, particularly the histone H3 lysine 27 (H3K27) demethylases JMJD3 and UTX, remain largely uncharacterized in melanoma. Here, I uncover that histone H3K27 demethylases, JMJD3 and UTX, play opposing roles in both primary tumor growth and metastasis in the context of melanoma. 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. By contrast, UTX suppresses the formation of a favorable tumor microenvironment, resulting in attenuation of melanoma progression and metastasis. Mechanistic investigations demonstrated that JMJD3 transcriptionally upregulated several targets of $NF- \kappa B$ 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, I found that BMP4, another JMJD3 target gene, regulated JMJD3 expression via a positive feedback mechanism. My findings reveal that UTX and JMJD3 play contrasting roles in both primary tumor growth and metastasis in the context of melanoma and further identify the molecular mechanisms underlying this interesting phenomenon.