Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis
| Autor: | Schmidt, Oxana, Nehls, Nadja, Prexler, Carolin, von Heyking, Kristina, Groll, Tanja, Pardon, Katharina, Garcia, Heathcliff D., Hensel, Tim, Gürgen, Dennis, Henssen, Anton G., Eggert, Angelika, Steiger, Katja, Burdach, Stefan, Richter, Günther H. S. |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Expression profiles
Cancer Research Research Correction Neoplasms. Tumors. Oncology. Including cancer and carcinogens Sarcoma Ewing Pathogenesis Histone Deacetylases Targeted therapy Mice Class I HDACs Cell Line Tumor Animals Humans 600 Technik Medizin angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit Ewing sarcoma RC254-282 Cell Proliferation |
| Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-16 (2021) Journal of Experimental & Clinical Cancer Research : CR |
| Popis: | Background Histone acetylation and deacetylation seem processes involved in the pathogenesis of Ewing sarcoma (EwS). Here histone deacetylases (HDAC) class I were investigated. Methods Their role was determined using different inhibitors including TSA, Romidepsin, Entinostat and PCI-34051 as well as CRISPR/Cas9 class I HDAC knockouts and HDAC RNAi. To analyze resulting changes microarray analysis, qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results Class I HDACs are constitutively expressed in EwS. Patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knockout of individual HDACs such as HDAC1 and HDAC2 inhibited invasiveness, and blocked local tumor growth in xenograft mice. Microarray analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while Entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with chemotherapeutics including Doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusions Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi is an interesting new treatment opportunity for this malignant disease. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02125-z. |
| Databáze: | OpenAIRE |
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