Targeting the EWSR1-FLI1 oncogene-induced protein kinase PKC-ß abolishes ewing sarcoma growth.
Cancer Res
; 72(17): 4494-503, 2012 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-22930730
ABSTRACT
Ewing sarcoma is a rare but aggressive disease most common in young adults. This cancer is driven by a unique chimeric fusion oncogene but targeted strategies have been elusive. Here we report the identification of the protein kinase PKC-ß (PRKCB) as a disease-specific druggable target for treatment of Ewing sarcoma. We found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer. PRKCB phosphorylated histone H3T6 to permit global maintenance of H3K4 trimethylation at a variety of gene promoters. PRKCB loss induced apoptosis in vitro and prevented tumor growth in vivo. Gene expression profiling revealed a strong overlap between genes modulated by EWSR1-FLI1 and PRKCB in regulating crucial signaling pathways. Taken together, our findings offer a preclinical proof-of-concept for PRKCB as a promising therapeutic target in Ewing sarcoma.
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Base de dados:
MEDLINE
Assunto principal:
Sarcoma de Ewing
/
Proteínas de Ligação a Calmodulina
/
Proteína Quinase C
/
Proteínas de Fusão Oncogênica
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Proteínas de Ligação a RNA
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Proteína Proto-Oncogênica c-fli-1
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article