Global Reduction of H3K4me3 Improves Chemotherapeutic Efficacy for Pediatric Ependymomas1
| Autor: | Lewis, Rebecca, Li, Yuping D, Hoffman, Lindsey, Hashizume, Rintaro, Gravohac, Gordan, Rice, Gavin, Wadhwani, Nitin R, Jie, Chunfa, Pundy, Tatiana, Mania-Farnell, Barbara, Mayanil, Chandra S, Soares, Marcelo B, Lei, Ting, James, Charles D, Foreman, Nicolas K, Tomita, Tadanori, Xi, Guifa |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Original article CPL carboplatin ChIP-PCR chromatin-immunoprecipitation coupled with real-time PCR Cell Survival Receptor ErbB-2 Primary Cell Culture CNS central nervous system Pediatrics Carboplatin Histones EMEM Eagle's Minimum Essential Medium Humans Cyclin D1 VCR vincristine Promoter Regions Genetic CIMP+ CpG island methylator positive Histone-Lysine N-Methyltransferase FFPE formalin-fixed paraffin-embedded Gene Expression Regulation Neoplastic EPN ependymoma Drug Resistance Neoplasm Ependymoma Vincristine Child Preschool PFS progression free survival TSS transcription start site MTS 3-(4 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium Female PTM posttranslational modification IRB institutional review board |
| Zdroj: | Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 1522-8002 |
| Popis: | BACKGROUND: Ependymomas (EPNs) are the third most common brain tumor in children. These tumors are resistant to available chemotherapeutic treatments, therefore new effective targeted therapeutics must be identified. Increasing evidence shows epigenetic alterations including histone posttranslational modifications (PTMs), are associated with malignancy, chemotherapeutic resistance and prognosis for pediatric EPNs. In this study we examined histone PTMs in EPNs and identified potential targets to improve chemotherapeutic efficacy. METHODS: Global histone H3 lysine 4 trimethylation (H3K4me3) levels were detected in pediatric EPN tumor samples with immunohistochemistry and immunoblots. Candidate genes conferring therapeutic resistance were profiled in pediatric EPN tumor samples with micro-array. Promoter H3K4me3 was examined for two candidate genes, CCND1 and ERBB2, with chromatin-immunoprecipitation coupled with real-time PCR (ChIP-PCR). These methods and MTS assay were used to verify a relationship between H3K4me3 levels and CCND1 and ERBB2, and to investigate cell viability in response to chemotherapeutic drugs in primary cultured pediatric EPN cells. RESULTS: H3K4me3 levels positively correlate with WHO grade malignancy in pediatric EPNs and are associated with progression free survival in patients with posterior fossa group A EPNs (PF-EPN-A). Reduction of H3K4me3 by silencing its methyltransferase SETD1A, in primary cultured EPN cells increased cell response to chemotherapy. CONCLUSIONS: Our results support the development of a novel treatment that targets H3K4me3 to increase chemotherapeutic efficacy in pediatric PF-EPN-A tumors. |
| Databáze: | OpenAIRE |
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