Abstract
Ezrin has been reported to be upregulated in many tumors and to participate in metastatic progression. No study has addressed epigenetic modification in the regulation of Ezrin gene expression, the importance of which is unknown. Here, we report that highly metastatic rhabdomyosarcoma (RMS) cells with high levels of Ezrin have elevated acetyl-H3-K9 and tri-methyl-H3-K4 as well as reduced DNA methylation at the Ezrin gene promoter. Conversely, poorly metastatic RMS cells with low levels of Ezrin have reduced acetyl-H3-K9 and elevated methylation. Thus epigenetic covalent modifications to histones within nucleosomes of the Ezrin gene promoter are linked to Ezrin expression, which in fact can be regulated by epigenetic mechanisms. Notably, treatment with histone deacetylase (HDAC) inhibitors or DNA demethylating agents could restore Ezrin expression and stimulate the metastatic potential of poorly metastatic RMS cells characterized by low Ezrin levels. However, the ability of epigenetic drugs to stimulate metastasis in RMS cells was inhibited by expression of an Ezrin-specific shRNA. Our data demonstrate the potential risk associated with clinical application of broadly acting covalent epigenetic modifiers, and highlight the value of combination therapies that include agents specifically targeting potent pro-metastatic genes.
Highlights
Tumor genesis and progression to metastasis are fueled through dysregulation of genes and/or signaling pathways resulting in abnormal cell functions and behaviors [1,2,3]
We found that RMS cells with elevated Ezrin expression and high metastatic potential had greater acetylation of histone H3 lysine 9 and tri-methylation of histone H3 lysine 4
Epigenetic modifications at the Ezrin gene locus are linked to its expression We previously reported that Ezrin expression was significantly increased in highly metastatic mouse RMS cell lines compared to poorly metastatic cell lines [7,21], but the mechanism by which the Ezrin gene is regulated, and the role of epigenetic modification, remain mostly unknown
Summary
Tumor genesis and progression to metastasis are fueled through dysregulation of genes and/or signaling pathways resulting in abnormal cell functions and behaviors [1,2,3]. Ezrin was determined to be a critical regulator of metastasis in pediatric sarcomas such as rhabdomyosarcoma (RMS) and osteosarcoma [7,8,9]. Ezrin is known to mediate multiple cellular activities including survival, adhesion and migration/invasion [16,17,18], thereby regulating tumor development and progression through signal transduction pathways involving protein kinase A, Rho, phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase (MAPK) and Src [16,17,18,19,20]. The function of Ezrin is well studied, the transcriptional regulation of Ezrin is poorly understood
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