A new metabolic gene signature in prostate cancer regulated by JMJD3 and EZH2.
A new metabolic gene signature in prostate cancer regulated by JMJD3 and EZH2.
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DOI：
10.18632/oncotarget.25182
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发表时间：
2018-05-04
期刊：
影响因子：
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通讯作者：
Bernard-Gallon D
中科院分区：
文献类型：
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作者：
Daures M;Idrissou M;Judes G;Rifaï K;Penault-Llorca F;Bignon YJ;Guy L;Bernard-Gallon D
组蛋白甲基化对于基因表达控制至关重要。组蛋白 3 (H3K27me3) 的三甲基化赖氨酸 27 由 JMJD3 去甲基酶和 EZH2 甲基转移酶活性之间的平衡控制。这种表观遗传标记已被证明在前列腺癌中失调，并且有证据表明前列腺癌中基因启动子上的 H3K27me3 富集。为了研究这种富集的影响，使用 TaqMan 低密度阵列 (TLDA) 对多个基因进行了转录组分析，将前列腺活检分为三个临床等级：正常 (n = 23) 和侵袭性不同的两个肿瘤组（格里森评分 ≤ 7 (n = 20) 和 > 7 (n = 19)）。方差分析表明，基因组的表达在肿瘤中上调，并与格里森评分相关，从而区分三个临床组。参与关键细胞过程的六个基因脱颖而出：JMJD3、EZH2、MGMT、TRA2A、U2AF1 和 RPS6KA2。染色质免疫沉淀证明 EZH2 和 JMJD3 在基因启动子上的搭配取决于疾病阶段。还在用 JMJD3 (GSK-J4) 或 EZH2 (DZNeP) 抑制剂处理的前列腺癌细胞系（DU 145、PC-3 和 LNCaP）上评估了基因组表达，以研究它们在基因调控中的参与。结果显示，细胞系 PTEN 状态下的 GSK-J4 敏感性存在差异，而细胞雄激素状态下的基因表达谱则相反。总之，我们的数据描述了 JMJD3 和 EZH2 对前列腺癌新基因特征的影响，这可能有助于确定前列腺癌的诊断和治疗靶点。
Histone methylation is essential for gene expression control. Trimethylated lysine 27 of histone 3 (H3K27me3) is controlled by the balance between the activities of JMJD3 demethylase and EZH2 methyltransferase. This epigenetic mark has been shown to be deregulated in prostate cancer, and evidence shows H3K27me3 enrichment on gene promoters in prostate cancer. To study the impact of this enrichment, a transcriptomic analysis with TaqMan Low Density Array (TLDA) of several genes was studied on prostate biopsies divided into three clinical grades: normal (n = 23) and two tumor groups that differed in their aggressiveness (Gleason score ≤ 7 (n = 20) and >7 (n = 19)). ANOVA demonstrated that expression of the gene set was upregulated in tumors and correlated with Gleason score, thus discriminating between the three clinical groups. Six genes involved in key cellular processes stood out: JMJD3, EZH2, MGMT, TRA2A, U2AF1 and RPS6KA2. Chromatin immunoprecipitation demonstrated collocation of EZH2 and JMJD3 on gene promoters that was dependent on disease stage. Gene set expression was also evaluated on prostate cancer cell lines (DU 145, PC-3 and LNCaP) treated with an inhibitor of JMJD3 (GSK-J4) or EZH2 (DZNeP) to study their involvement in gene regulation. Results showed a difference in GSK-J4 sensitivity under PTEN status of cell lines and an opposite gene expression profile according to androgen status of cells. In summary, our data describe the impacts of JMJD3 and EZH2 on a new gene signature involved in prostate cancer that may help identify diagnostic and therapeutic targets in prostate cancer.