Abstract 5268: Stimulated metastasis after treatment with epigenetic drugs through up-regulation of Ezrin
| Autor: | Yanlin Yu |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
biology business.industry macromolecular substances medicine.disease environment and public health Pediatric cancer Metastasis Demethylating agent chemistry.chemical_compound Histone Ezrin Oncology chemistry DNA methylation Cancer research biology.protein medicine Histone deacetylase Epigenetics business |
| Zdroj: | Cancer Research. 70:5268-5268 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am10-5268 |
| Popis: | Stimulated metastasis after treatment with epigenetic drugs through up-regulation of Ezrin Yanlin Yu, Pingyao Zeng, Jingbo Xiang, Shelley L. Berger and Glenn Merlino Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland The metastases at distant sites are still the main cause of death in cancer patients. New prognostic markers are urgently needed to assess the risk for developing metastasis, and novel therapeutic strategies are needed to treat this deadly disease. Epigenetic drugs such as histone deacetylase inhibitors (HDACis) and inhibitors of DNA methylation are emerging as a new class of anticancer agents and are in several ongoing patient treatment regimens. However, those drugs are thought to be “dirty drugs”, affecting many pathways. Previously, we identified Ezrin as a critical regulator of metastasis in a mouse model of the pediatric cancer rhabdomyosarcoma (RMS) (Yu, et al. Nature Medicine, 2004; Yu, et al. Cacner Res, 2006). In the current study, we examined the status of histone modification at the Ezrin gene chromatin locus and of methylation at the Ezrin promoter in highly and poorly metastatic RMS cell lines. Our results showed that RMS cells with high-level Ezrin and high metastatic potential have elevated acetylation of histone H3 lysine 9 (H3K9) and less methylation at the Ezrin promoter. In contrast, RMS cells with low-level Ezrin and poor metastatic potential have reduced acetylation of H3K9 and elevated methylation at the Ezrin promoter. Our data demonstrate that epigenetic covalent modifications to histones within nucleosomes of the Ezrin gene promoter are linked to Ezrin expression, and suggest that epigenetic regulation may affect the expression of Ezrin, thereby regulating metastasis. We further found that treatment with HDACi TSA or DNA demethylating agent 5-aza can restore expression of Ezrin and stimulate the metastatic potential of poorly metastatic cells with low Ezrin levels. Notably, the combination of Ezrin shRNA and HDACi can significantly inhibit this metastasis. This finding provides new mechanistic and therapeutic insights of epigenetic drugs in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5268. |
| Databáze: | OpenAIRE |
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