Comprehensive profiling of JMJD3 in gastric cancer and its influence on patient survival

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.

Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma

“…GSK-J4 has been used to treat many kinds of tumors such as Tcell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia, diffuse large B-cell lymphoma, DIPG, neuroblastoma, prostate cancer, and gastric cancer (10,(35)(36)(37)(38)(39)(40)(41). However, GSK-J4 is not yet in clinical development.…”

“…The major challenge of GSK-J4 in clinical development is that GSK-J4 is a prodrug and is rapidly converted to active drug GSK-J1 in vivo (10,42). The highly polar GSK-J1 compound has restricted cellular permeability (41). Further development for stabilizing GSK-J4 in vivo would be required for clinical application for this compound.…”

JMJD8 Promotes Malignant Progression of Lung Cancer by Maintaining EGFR Stability and EGFR/PI3K/AKT Pathway Activation

“…In oral squamous cell carcinoma, JMJD5 was found to induce apoptosis by influencing p53/nuclear factor (NF)-κB signaling 16 . In gastric cancer, high JMJD3 expression is associated with a reduced overall survival rate 17 .…”

Long noncoding RNA ARHGAP27P1 inhibits gastric cancer cell proliferation and cell cycle progression through epigenetically regulating p15 and p16

“…On the other hand, an oncogenic role of JMJD3 has been documented in the case of T-cell acute lymphocytic leukemia (T-ALL) and myelodysplastic syndrome (MDS) [45, 46], which was largely attributed to its specific partnership with NF-κB and NOTCH, two transcription factors whose overactivations are highly associated with the induction of multiple types of inflammatory cytokines and the proliferation of T cells. JMJD3 has also been recently shown upregulated in GC and ESCC, and its high expression predicted unfavorable survival [41, 42]. These observations implicate the existence of uncharacterized regulatory effects of JMJD3 on cell differentiation, survival, and proliferation, and suggest that the expression patterns of JMJD3 are context and cancer type specific.…”