CRISPR activation screen identifies TGFß-associated PEG10 as a crucial tumor suppressor in Ewing sarcoma.
Sci Rep
; 12(1): 10671, 2022 06 23.
Article
em En
| MEDLINE
| ID: mdl-35739280
ABSTRACT
As the second most common pediatric bone and soft tissue tumor, Ewing sarcoma (ES) is an aggressive disease with a pathognomonic chromosomal translocation t(11;22) resulting in expression of EWS-FLI1, an "undruggable" fusion protein acting as transcriptional modulator. EWS-FLI1 rewires the protein expression in cancer cells by activating and repressing a multitude of genes. The role and contribution of most repressed genes remains unknown to date. To address this, we established a CRISPR activation system in clonal SKNMC cell lines and interrogated a custom focused library covering 871 genes repressed by EWS-FLI1. Among the hits several members of the TGFß pathway were identified, where PEG10 emerged as prime candidate due to its strong antiproliferative effect. Mechanistic investigations revealed that PEG10 overexpression caused cellular dropout via induction of cell death. Furthermore, non-canonical TGFß pathways such as RAF/MEK/ERK, MKK/JNK, MKK/P38, known to lead to apoptosis or autophagy, were highly activated upon PEG10 overexpression. Our study sheds new light onto the contribution of TGFß signalling pathway repression to ES tumorigenesis and suggest that its re-activation might constitute a novel therapeutic strategy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sarcoma de Ewing
/
Proteínas de Ligação a RNA
/
Tumores Neuroectodérmicos Primitivos Periféricos
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Proteínas de Ligação a DNA
/
Proteínas Reguladoras de Apoptose
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Child
/
Humans
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Suíça