Strong evidences support the critical role of Jumonji domain containing 6 (JMJD6) in progression of breast cancer. Here we explore potential partners that coregulate gene expression, to understand additional pathways that are activated by higher amounts of JMJD6. We used Gene Set Enrichment Analysis (GSEA) data to identify factors that display gene expression similar to cells treated with JMJD6 siRNA. Using chromatin immunoprecipitations (ChIP) against genomic regions that bind JMJD6 identified by in house and public database Encyclopaedia of DNA Elements (ENCODE), we confirmed JMJD6 occupancy by ChIP PCR. We tested the association of co-regulated genes with patient prognosis using The Cancer Genome Atlas (TCGA) datasets. JMJD6 profiles overlapped with those of Enhancer of Zeste homolog 2 (EZH2) and together they appear to co-regulate a unique cassette of genes in both ER+ and ER- cells. 496 genes including aurora kinases, which are currently being tested as novel therapeutic targets in breast cancer were co-regulated in MDA MB 231 cells. JMJD6 and EZH2 neither inter-regulated nor physically interacted with one another. Since both proteins are chromatin modulators, we performed ChIP linked PCR analysis and show that JMJD6 bound in the neighbourhood of co-regulated genes, though EZH2 data did not show any peaks within 100 kb of these sites. Alignment of binding site sequences suggested that atleast two types of binding partners could offer their DNA binding properties to enrich JMJD6 at regulatory sites. In clinical samples, JMJD6 and EZH2 expression significantly correlated in both normal and tumor samples, however the strongest correlation was observed in triple-negative breast cancer (TNBC) subtype. Co-expression of JMJD6 and EZH2 imposed poorer prognosis in breast cancer. JMJD6 and EZH2 regulate the same crucial cell cycle regulatory and therapeutic targets but their mechanisms appear to be independent of each other. Blocking of a single molecule may not axe cell proliferation completely and blocking both JMJD6 and EZH2 simultaneously may be more effective in breast cancer patients.

中文翻译：

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EZH2和JMJD6均调节乳腺癌细胞周期基因

有力的证据支持含有Jumonji结构域的6（JMJD6）在乳腺癌进展中的关键作用。在这里，我们探索潜在的合作伙伴，它们可以整合基因表达，以了解更多数量的JMJD6激活的其他途径。我们使用基因集富集分析（GSEA）数据来鉴定显示与JMJD6 siRNA处理的细胞相似的基因表达的因子。使用针对与JMJD6结合的基因组区域的染色质免疫沉淀（ChIP），通过内部和公共数据库《 DNA元素百科全书》（ENCODE）鉴定，我们通过ChIP PCR确认了JMJD6的存在。我们使用癌症基因组图谱（TCGA）数据集测试了共调控基因与患者预后的关联。JMJD6谱与Zeste同源物2（EZH2）的增强子重叠，它们似乎共同调节ER +和ER-细胞中独特的基因盒。MDA MB 231细胞中共调节了496个基因（包括极光激酶），目前正在将其作为乳腺癌的新型治疗靶标进行测试。JMJD6和EZH2既不相互调控也不相互物理相互作用。由于这两种蛋白都是染色质调节剂，因此我们进行了ChIP连锁PCR分析，并显示JMJD6结合在共同调控的基因附近，尽管EZH2数据未显示这些位点100 kb内的任何峰。结合位点序列的比对表明，至少两种类型的结合伴侣可以提供其DNA结合特性，以丰富JMJD6的调控位点。在临床样本中 JMJD6和EZH2表达在正常和肿瘤样品中均显着相关，但是在三阴性乳腺癌（TNBC）亚型中观察到最强的相关性。JMJD6和EZH2的共表达在乳腺癌中预后较差。JMJD6和EZH2调节相同的关键细胞周期调节和治疗靶标，但它们的机制似乎彼此独立。阻断单个分子可能无法完全阻止细胞增殖，同时阻断JMJD6和EZH2在乳腺癌患者中可能更有效。JMJD6和EZH2调节相同的关键细胞周期调节和治疗靶标，但它们的机制似乎彼此独立。阻断单个分子可能无法完全阻止细胞增殖，同时阻断JMJD6和EZH2在乳腺癌患者中可能更有效。JMJD6和EZH2调节相同的关键细胞周期调节和治疗靶标，但它们的机制似乎彼此独立。阻断单个分子可能无法完全阻止细胞增殖，同时阻断JMJD6和EZH2在乳腺癌患者中可能更有效。