Abstract
Histone methylation is thought to control the regulation of genetic program and the dysregulation of it has been found to be closely associated with cancer. JMJD3 has been identified as an H3K27 demethylase and its role in cancer development is context specific. The role of JMJD3 in gastric cancer (GC) has not been examined. In this study, JMJD3 expression was determined. The prognostic significance of JMJD3 and its association with clinical parameters were evaluated. JMJD3 dysregulation mechanism and targets were analyzed. The effect of JMJD3 mutation was determined by functional study. Results showed that JMJD3 was overexpressed in different patient cohorts and also by bioinformatics analysis. High JMJD3 expression was correlated with shortened overall survival in patients with GC and was an independent prognosis predictor. Genetic aberration and DNA methylation might be involved in the deregulation of JMJD3 in GC. Downstream network of JMJD3 was analyzed and several novel potential targets were identified. Furthermore, functional study discovered that both demethylase-dependent and demethylase-independent mechanisms were involved in the oncogenic role of JMJD3 in GC. Importantly, histone demethylase inhibitor GSK-J4 could reverse the oncogenic effect of JMJD3 overexpression. In conclusion, our study report the oncogenic role of JMJD3 in GC for the first time. JMJD3 might serve as an important epigenetic therapeutic target and/or prognostic predictor in GC.
Highlights
Epigenetic modifications play an important role in cancer initiation and progression[1]
JMJD3 expression levels are lower in colorectal cancer relative to normal tissues[7]
Our result demonstrated that hyper mutation (Fig. 2B) and MLH1 silencing (Fig. 2C) were associated with lower JMJD3 expression (p < 0.05), supporting the oncogenic role of JMJD3
Summary
Epigenetic modifications play an important role in cancer initiation and progression[1]. Histone methylation is an essential epigenetic phenomenon and the dysregulation of it is associated with the processes of cancer occurrence/progression[2]. Many studies have demonstrated that JMJD3 is involved in cancer progression via regulation of several cellular processes, such as proliferation, senescence, and apoptosis[1,3,5]. JMJD3 expression levels are lower in colorectal cancer relative to normal tissues[7]. Shen et al reported that both JMJD3 mRNA and protein levels were significantly elevated in renal carcinoma compared to adjacent normal tissue[8]. There is no published study on the role of JMJD3 in gastric cancer (GC). Elucidation of the role of JMJD3 in GC may lead to new therapeutic approach for the treatment of this disease
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