JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells.

Détails

ID Serval
serval:BIB_DA4FFBE68A20
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells.
Périodique
Oncogene
Auteur(s)
Walters Z.S., Villarejo-Balcells B., Olmos D., Buist T.W., Missiaglia E., Allen R., Al-Lazikani B., Garrett M.D., Blagg J., Shipley J.
ISSN
1476-5594 (Electronic)
ISSN-L
0950-9232
Statut éditorial
Publié
Date de publication
2014
Peer-reviewed
Oui
Volume
33
Numéro
9
Pages
1148-1157
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublishPublication Type Journal Article. Research Support
Résumé
Rhabdomyosarcomas (RMS) are the most frequent soft-tissue sarcoma in children and characteristically show features of developing skeletal muscle. The alveolar subtype is frequently associated with a PAX3-FOXO1 fusion protein that is known to contribute to the undifferentiated myogenic phenotype of RMS cells. Histone methylation of lysine residues controls developmental processes in both normal and malignant cell contexts. Here we show that JARID2, which encodes a protein known to recruit various complexes with histone-methylating activity to their target genes, is significantly overexpressed in RMS with PAX3-FOXO1 compared with the fusion gene-negative RMS (t-test; P < 0.0001). Multivariate analyses showed that higher JARID2 levels are also associated with metastases at diagnosis, independent of fusion gene status and RMS subtype (n = 120; P = 0.039). JARID2 levels were altered by silencing or overexpressing PAX3-FOXO1 in RMS cell lines with and without the fusion gene, respectively. Consistent with this, we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein. Silencing JARID2 resulted in reduced cell proliferation coupled with myogenic differentiation, including increased expression of Myogenin (MYOG) and Myosin Light Chain (MYL1) in RMS cell lines representative of both the alveolar and embryonal subtypes. Induced myogenic differentiation was associated with a decrease in JARID2 levels and this phenotype could be rescued by overexpressing JARID2. Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent on EED, a core component of the polycomb repressive complex 2 (PRC2). Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS. JARID2 and other components of PRC2 may represent novel therapeutic targets for treating RMS patients.
Mots-clé
Cell Differentiation/genetics, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic/genetics, Histone Demethylases/genetics, Histone Demethylases/metabolism, Humans, Muscle Development/genetics, Myogenin/genetics, Myogenin/metabolism, Nuclear Proteins/genetics, Nuclear Proteins/metabolism, Oncogene Proteins, Fusion/genetics, Oncogene Proteins, Fusion/metabolism, Paired Box Transcription Factors/genetics, Paired Box Transcription Factors/metabolism, Polycomb Repressive Complex 2/genetics, Polycomb Repressive Complex 2/metabolism, Promoter Regions, Genetic/genetics, Rhabdomyosarcoma/genetics, Rhabdomyosarcoma/pathology, Transcription Factors/genetics, Transcription Factors/metabolism, Transcription, Genetic/genetics, Tumor Suppressor Proteins/genetics, Tumor Suppressor Proteins/metabolism
Pubmed
Web of science
Création de la notice
30/05/2014 18:59
Dernière modification de la notice
03/03/2018 21:54
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