MPP8-Mediated Epigenetic Network and Its Roles in Tumor Progression

MPP8介导的表观遗传网络及其在肿瘤进展中的作用 表观遗传学通常被定义为发生在基因表达上的可遗传变化，而不是 DNA序列。两种最广泛研究的表观遗传机制，组蛋白修饰和DNA 甲基化是更广泛的表观遗传‘密码’的一部分，它决定了基因组区域的转录潜力。 因此，表观遗传修饰对于控制基因表达模式和细胞特性是必不可少的，同时 这些过程的中断可能会导致基因功能改变和恶性细胞转化。作为两个人 主要的抑制性表观遗传修饰，组蛋白H3K9甲基化和DNA甲基化已经明显 与建立和维持肿瘤进展过程中的基因抑制模式有关。与一致 这一概念，我们最近的研究表明，一种新的甲基H3H9结合蛋白MPP8具有重要的功能 在EMT(上皮向间充质转化)中，赋予上皮性肿瘤细胞 迁移和侵袭能力与转移能力相关。MPP8显示升高的 MPP8基因在转移性乳腺癌和肺癌组织中的表达 癌细胞重建上皮表型，伴随着显著减少迁移和侵袭 超能力。在分子水平上，MPP8直接靶向E-钙粘蛋白启动子并抑制这一关键的EMT 调整器。MPP8还与H3K9 MTase G9a/GLP和从头开始的DNMT3A相互作用，重要的是，与新兵 DNMT3A引导E-钙粘蛋白CpG岛上的DNA甲基化。MPP8蛋白相互作用特性的研究 进一步揭示了G9a/GLP在K47位甲基化DNMT3A以及它们自己的N-末端赖氨酸。所有的 由此产生的甲基化标记在体外和体内都被MPP8识别，表明MPP8协调 肿瘤抑制基因H3K9甲基化和DNA甲基化的新型表观遗传复合体 沉默。此外，我们还证明了MPP8和G9a与主要的EMT激活密切相关 转录因子ZEB1。这些结果共同表明了EMT和肿瘤过程中的一种新的抑制途径 进展，其中ZEB1招募G9a-MPP8-DNMT3A复合体来建立H3K9和DNA甲基化 用于转录沉默各种上皮基因。为了扩展这项研究，我们建议进行进一步的实验 阐明该途径的分子机制，了解DNMT3A- K47甲基化。我们还将评估MPP8在EMT和肿瘤进展中的重要性。 活着。拟议研究的完成不仅将对我们对表观遗传学的理解产生重大影响 调控肿瘤进展，但也促进了可能的表观遗传策略的发展 癌症治疗。

MPP8-Mediated Epigenetic Network and Its Roles in Tumor Progression Epigenetics are commonly defined as heritable changes in gene expression that occur without changes in DNA sequence. Two of the most extensively studied epigenetic mechanisms, histone modifications and DNA methylation are part of broader epigenetic 'code' that dictates the transcriptional potential of genomic domains. Therefore, epigenetic modifications are essential to control gene expression patterns and cell identity while disruption of these processes can lead to altered gene function and malignant cellular transformation. As two major repressive epigenetic modifications, histone H3K9 methylation and DNA methylation have been clearly implicated in establishing and maintaining gene repression patterns during tumor progression. Consistent with this notion, our recent studies suggest that a novel methyl-H3H9 binding protein MPP8 has important functions in EMT (epithelial-to-mesenchymal transition), an essential program to endow epithelial tumor cells with migratory and invasive capabilities associated with metastatic competence. MPP8 displays an elevated expression in different human primary cancer tissues while knockdown of MPP8 in metastatic breast and lung cancer cells re-establishes epithelial phenotypes attended by a significantly reduces migration and invasion abilities. At the molecular level, MPP8 directly targets E-cadherin promoter and represses this key EMT regulator. MPP8 also interacts with H3K9 MTases G9a/GLP and de novo DNMT3A, and importantly, recruits DNMT3A to direct DNA methylation on E-cadherin CpG island. Characterization of MPP8 protein interactions further reveals that G9a/GLP methylate DNMT3A at K47 as well as their own N-terminal lysines. All the resultant methylation marks are recognized by MPP8 in vitro and in vivo, suggesting that MPP8 coordinates a novel epigenetic complex which couples H3K9 methylation and DNA methylation for tumor suppressor gene silencing. Furthermore, we demonstrate that MPP8 and G9a robustly associate with a major EMT-activating transcription factor ZEB1. These results together suggest a novel repression pathway during EMT and tumor progression, in which ZEB1 recruits G9a-MPP8-DNMT3A complex to establish H3K9 and DNA methylations for transcriptional silencing of various epithelial genes. To extend this study, we propose further experiments to elucidate molecular mechanisms of this pathway and to understand the functional significance of DNMT3A- K47 methylation. We will also assess the importance of MPP8 in EMT and tumor progression in vitro and in vivo. Completion of the proposed studies will not only significantly impact on our understanding of epigenetic regulations in tumor progression, but also facilitate the development of possible epigenetic strategies for the cancer treatment.