H3K27 Demethylase JMJD3 Employs the NF-κB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote 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 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-kB 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.

Histone demethylase JMJD3 regulates fibroblast‐like synoviocyte‐mediated proliferation and joint destruction in rheumatoid arthritis

“…Therefore, the targeting of hyperplasia FLS highlights the therapeutic potential for RA. As one of the histone demethylases, JMJD3 is associated with tumor cell proliferation and metastasis in different types of cancer (28,29). In this study, we found that inhibition of JMJD3 strongly reduced cell proliferation, migration, and invasion.…”

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

“…It ranks as the fifth most common cancer for male and the seventh most common malignancy in female (2,3). In recent years, a large number of studies have focused on the pathogenesis of MM, and deregulation of oncogenes and tumor suppressors have been reported to play key roles in the development and progression of MM (4,5). However, the detailed molecular mechanism underlying MM still remains largely unclear.…”

Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B

“…The sphere-forming capability of various SCC cell lines in cell-cycle control, senescence, and differentiation, and may play a role in cancer development in a context-dependent manner (21)(22)(23). In fact, KDM6B expression is upregulated in several malignancies, such as Hodgkin's lymphoma (24), breast cancer (25), gliomas (26), melanoma (27), and renal cell carcinoma (28), while it is suppressed in others, including lung adenocarcinoma and squamous cell carcinoma (29), colon cancer (30,31), and liver and pancreatic cancers (32). While inactivating KDM6B gene mutations are only found in 1%-3% of SCCs (cBioPortal for Cancer Genomics; http:// www.cbioportal.org), the gene, like NOTCH1, has been implicated as a positive determinant of squamous cell differentiation (33).…”