The University of Southampton
University of Southampton Institutional Repository

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

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

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.

Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Enhancer of Zeste Homolog 2 Protein, Gene Expression Regulation, Neoplastic, Histone Demethylases, Humans, Muscle Development, Myogenin, Nuclear Proteins, Oncogene Proteins, Fusion, Paired Box Transcription Factors, Polycomb Repressive Complex 2, Promoter Regions, Genetic, Promyelocytic Leukemia Protein, Rhabdomyosarcoma, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins, Journal Article, Research Support, Non-U.S. Gov't
0950-9232
1148-1157
Walters, Z S
e1ccd35d-63a9-4951-a5da-59122193740d
Villarejo-Balcells, B
1f136e7d-2aec-49c9-8dcc-46c5b5f268bc
Olmos, D
23057019-96bf-461f-9cd4-e3444f0a612e
Buist, T W S
918dab38-54ad-410b-9700-3920bb87dc81
Missiaglia, E
5c63d29e-3aad-4bc0-82ec-aa7d18896207
Allen, R
956a918f-278c-48ef-8e19-65aa463f199a
Al-Lazikani, B
45af8a02-14ec-4de2-83c4-93aa672c9dcd
Garrett, M D
7be3e861-0ae2-4d50-963e-42f3004a6dee
Blagg, J
b7b83538-8eee-4bff-be75-cffd65e365e5
Shipley, J
2c53e7f0-8721-4460-8168-4fde68fe85d1
Walters, Z S
e1ccd35d-63a9-4951-a5da-59122193740d
Villarejo-Balcells, B
1f136e7d-2aec-49c9-8dcc-46c5b5f268bc
Olmos, D
23057019-96bf-461f-9cd4-e3444f0a612e
Buist, T W S
918dab38-54ad-410b-9700-3920bb87dc81
Missiaglia, E
5c63d29e-3aad-4bc0-82ec-aa7d18896207
Allen, R
956a918f-278c-48ef-8e19-65aa463f199a
Al-Lazikani, B
45af8a02-14ec-4de2-83c4-93aa672c9dcd
Garrett, M D
7be3e861-0ae2-4d50-963e-42f3004a6dee
Blagg, J
b7b83538-8eee-4bff-be75-cffd65e365e5
Shipley, J
2c53e7f0-8721-4460-8168-4fde68fe85d1

Walters, Z S, Villarejo-Balcells, B, Olmos, D, Buist, T W S, Missiaglia, E, Allen, R, Al-Lazikani, B, Garrett, M D, Blagg, J and Shipley, J (2014) JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells. Oncogene, 33 (9), 1148-1157. (doi:10.1038/onc.2013.46).

Record type: Article

Abstract

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.

This record has no associated files available for download.

More information

Accepted/In Press date: 11 January 2013
e-pub ahead of print date: 25 February 2013
Published date: 27 February 2014
Keywords: Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Enhancer of Zeste Homolog 2 Protein, Gene Expression Regulation, Neoplastic, Histone Demethylases, Humans, Muscle Development, Myogenin, Nuclear Proteins, Oncogene Proteins, Fusion, Paired Box Transcription Factors, Polycomb Repressive Complex 2, Promoter Regions, Genetic, Promyelocytic Leukemia Protein, Rhabdomyosarcoma, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 416323
URI: http://eprints.soton.ac.uk/id/eprint/416323
ISSN: 0950-9232
PURE UUID: 5c499a0d-3efe-4f51-83b8-5571200c3d53
ORCID for Z S Walters: ORCID iD orcid.org/0000-0002-1835-5868

Catalogue record

Date deposited: 13 Dec 2017 17:30
Last modified: 16 Mar 2024 04:32

Export record

Altmetrics

Contributors

Author: Z S Walters ORCID iD
Author: B Villarejo-Balcells
Author: D Olmos
Author: T W S Buist
Author: E Missiaglia
Author: R Allen
Author: B Al-Lazikani
Author: M D Garrett
Author: J Blagg
Author: J Shipley

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×