Abstract
The Jumonji domain-containing chromatin remodeling factor JMJD3 has important roles in development and cancer. Here, we report a pivotal role for JMJD3 in sustaining the phenotype of aggressive hepatocellular carcinomas. Expression levels of JMJD3 in clinical specimens of hepatocellular carcinoma correlated inversely with patient survival. In hepatocellular carcinoma cells, we found that enforcing its overexpression induced epithelial-mesenchymal transition (EMT), invasive migration, stem cell-like traits, and metastatic properties. Conversely, silencing JMJD3 in hepatocellular carcinoma cells overexpressing it inhibited these aggressive phenotypes. Mechanistically, JMJD3 modulated H3K27me3 in the SLUG gene promoter, a histone mark associated with active SLUG transcription. SLUG silencing blocked JMJD3-induced EMT, stemness, and metastasis. Furthermore, SLUG expression in hepatocellular carcinoma clinical specimens correlated positively with JMJD3 expression. Our results establish JMJD3 as a critical driver of hepatocellular carcinoma stem cell-like and metastatic behaviors, with implications for prognosis and treatment. Cancer Res; 76(22); 6520-32. ©2016 AACR.
Highlights
Hepatocellular carcinoma is a highly lethal malignancy with increasing global incidence [1, 2]
To determine the relation between histone demethylases and hepatocellular carcinoma metastasis, we investigated the expression of common histone demethylases, namely, JMJD1A, JMJD2A, JMJD2B, JMJD2C, JMJD2D, JMJD3, and JMJD6, in hepatocellular carcinomas with or without distant metastasis tissues through qRT-PCR
We found that JMJD3 was significantly upregulated in hepatocellular carcinomas with distant metastasis compared with other histone demethylases (Fig. 1A)
Summary
Hepatocellular carcinoma is a highly lethal malignancy with increasing global incidence [1, 2]. Histone proteins are susceptible to various covalent modifications, including acetylation, phosphorylation, methylation, and ubiquitination, which participate in the establishment and maintenance of gene expression patterns in any cell type of an organism. The methylation of histone H3 lysine 27 (H3K27) is an important epigenetic modification found at the promoters of many developmentally important genes; and H3K27 is involved in cancer [4, 5]. The Jumonji domain–containing protein 3 (JMJD3) catalyzes the transition of H3K27me and H3K27me to H3K27me, from a repressive to an active chromatin conformation [7]. This histone demethylase activity is implicated between cellular proliferation and differentiation to establish cell fate during development [7, 8]. Self-renewal within malignancies may reside in a subset of cancer cells called cancer stem cells (CSC) with stem cell–like properties [12, 13]
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