UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells.
UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells.
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DOI：
10.1158/0008-5472.can-13-1896
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发表时间：
2014-03-15
期刊：
影响因子：
11.2
通讯作者：
Lee MG
中科院分区：
文献类型：
--
作者：
Kim JH;Sharma A;Dhar SS;Lee SH;Gu B;Chan CH;Lin HK;Lee MG
组蛋白甲基转移酶和去甲基化酶可逆地调节组蛋白赖氨酸甲基化，这被认为是与基因调控相关的关键表观遗传标记。最近，组蛋白甲基化修饰剂对基因表达的异常调节已成为肿瘤发生的重要机制。然而，组蛋白甲基转移酶和去甲基化酶如何共同调节癌细胞特征的转录谱仍然很大程度上未知。在这里，我们发现在乳腺癌细胞中，组蛋白 H3 赖氨酸 27 (H3K27) 去甲基化酶 UTX（也称为 KDM6A）正向调节与细胞增殖和侵袭相关的基因表达程序。大多数 UTX 控制的基因，包括一组癌基因和促转移基因，均受到 H3K4 甲基转移酶混合谱系白血病 4（MLL4，也称为 ALR、KMT2D 和 MLL2）的共同调节。 UTX 与 MLL4 的 C 末端区域相互作用。 UTX 敲低导致体外和小鼠异种移植模型中乳腺癌细胞的增殖和侵袭性显着降低。 MLL4 敲除细胞可复制 UTX 耗尽细胞的这种有缺陷的细胞特征。 UTX 催化的三甲基化 H3K27 去甲基化和 MLL4 介导的 H3K4 三甲基化在 UTX 和 MLL4 的共同靶基因上相互依赖地发生。临床上，高水平的UTX或MLL4与乳腺癌患者的不良预后相关。总而言之，这些发现揭示了组蛋白甲基转移酶和组蛋白去甲基化酶对基因表达程序的协调调节与乳腺癌细胞的增殖和侵袭有关。
Histone methyltransferases and demethylases reversibly modulate histone lysine methylation, which is considered a key epigenetic mark associated with gene regulation. Recently, aberrant regulation of gene expression by histone methylation modifiers has emerged as an important mechanism for tumorigenesis. However, it remains largely unknown how histone methyltransferases and demethylases co-regulate transcriptional profiles for cancer cell characteristics. Here, we show that in breast cancer cells, the histone H3 lysine 27 (H3K27) demethylase UTX (also known as KDM6A) positively regulates gene expression programs associated with cell proliferation and invasion. The majority of UTX-controlled genes, including a cohort of oncogenes and pro-metastatic genes, are co-regulated by the H3K4 methyltransferase mixed lineage leukemia 4 (MLL4, also called ALR, KMT2D, and MLL2). UTX interacted with a C-terminal region of MLL4. UTX knockdown resulted in significant decreases in the proliferation and invasiveness of breast cancer cells in vitro and in a mouse xenograft model. Such defective cellular characteristics of UTX-depleted cells were phenocopied by MLL4 knockdown cells. UTX-catalyzed demethylation of trimethylated H3K27 and MLL4-mediated trimethylation at H3K4 occurred inter-dependently at co-target genes of UTX and MLL4. Clinically, high levels of UTX or MLL4 were associated with poor prognosis in breast cancer patients. Taken together, these findings uncover that coordinated regulation of gene expression programs by a histone methyltransferase and a histone demethylase is coupled to the proliferation and invasion of breast cancer cells.