Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth
| Autor: | Timothy S. Mulvihill, Venkataswamy Sorna, Emily R. Theisen, Savita Sankar, Laura M. Hoffman, Sunil Sharma, Mary C. Beckerle, Stephen L. Lessnick, Jared Bearss |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Oncogene Proteins Fusion Apoptosis Bone Neoplasms Sarcoma Ewing medicine.disease_cause Article law.invention Epigenesis Genetic Proto-Oncogene Protein c-ets-1 Transcriptional Regulator ERG law Cell Line Tumor medicine Humans Epigenetics Cell Proliferation Histone Demethylases biology Cell growth Proto-Oncogene Protein c-fli-1 Cancer medicine.disease Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Oncology biology.protein Cancer research Trans-Activators Suppressor Demethylase Sarcoma RNA-Binding Protein EWS Carcinogenesis |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 20(17) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: Ewing sarcoma is a pediatric bone tumor that absolutely relies on the transcriptional activity of the EWS/ETS family of fusion oncoproteins. While the most common fusion, EWS/FLI, utilizes lysine-specific demethylase 1 (LSD1) to repress critical tumor suppressors, small-molecule blockade of LSD1 has not yet been thoroughly explored as a therapeutic approach for Ewing sarcoma. We therefore evaluated the translational potential of potent and specific LSD1 inhibition with HCI2509 on the transcriptional program of both EWS/FLI and EWS/ERG as well as the downstream oncogenic phenotypes driven by EWS/ETS fusions in both in vitro and in vivo models of Ewing sarcoma. Experimental Design: RNA-seq was used to compare the transcriptional profiles of EWS/FLI, EWS/ERG, and treatment with HCI2509 in both EWS/FLI- and EWS/ERG-containing cell lines. We then evaluated morphologic phenotypes of treated cells with immunofluorescence. The induction of apoptosis was evaluated using caspase-3/7 activation and TUNEL staining. Colony forming assays were used to test oncogenic transformation and xenograft studies with patient-derived cell lines were used to evaluate the effects of HCI2509 on tumorigenesis. Results: HCI2509 caused a dramatic reversal of both the up- and downregulated transcriptional profiles of EWS/FLI and EWS/ERG accompanied by the induction of apoptosis and disruption of morphologic and oncogenic phenotypes modulated by EWS/FLI. Importantly, HCI2509 displayed single-agent efficacy in multiple xenograft models. Conclusions: These data support epigenetic modulation with HCI2509 as a therapeutic strategy for Ewing sarcoma, and highlight a critical dual role for LSD1 in the oncogenic transcriptional activity of EWS/ETS proteins. Clin Cancer Res; 20(17); 4584–97. ©2014 AACR. |
| Databáze: | OpenAIRE |
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