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MPP8-Mediated Epigenetic Network and Its Roles in Tumor Progression

Jia Fang

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National Institutes of Health (NIH)
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.

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