PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation

Authors

Elizabeth Charytonowicz, Edith Cowan University
Igor Matushansky, Edith Cowan University
Mireia Castillo-Martin, Edith Cowan University
Marc Ladanyi, Edith Cowan University
Carlos Cordon-Cardo, Edith Cowan University
Josep Domingo-Domenech, Edith Cowan University
Melanie Ziman, Edith Cowan UniversityFollow

Document Type

Journal Article

Faculty

Faculty of Computing, Health and Science

School

School of Medical Sciences

RAS ID

13251

Comments

Charytonowicz, E. , Matushansky, I., Castillo-Martin, M., Ladanyi, M., Cordon-Cardo, C., Domingo-Domenech, J., & Ziman, M. R. (2011). PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation. Clinical and Translational Oncology, 14(3), 197-206. Available here

Abstract

OBJECTIVE: Alveolar rhabdomyosarcomas (ARMS) are characterised by a PAX3/7-FKHR translocation, which is presumed to promote a differentiation arrest in the myogenic lineage, in which setting secondary genetic events occur, resulting in sarcomagenesis. The aim of this study was to identify the mechanism by which PAX3/7-FKHR expression results in a myogenic differentiation block, as discrete from the secondary genetic events that complete the sarcomagenic process. METHODS: We performed a novel differential gene expression analysis comparing normal mesenchymal stem cells with previously generated non-tumorigenic mesenchymal stem cells expressing the PAX7-FKHR fusion gene, as well as with a known tumorigenic, PAX7-FKHR-expressing ARMS cell line, CW9019. RESULTS: This novel analysis uncovered the upregulation of the NF-kappaB pathway as a function of PAX3/7-FKHR expression, but distinct from the secondary sarcomagenic process; thus implicating NF-kappaB as a mediator of the PAX3/7-FKHR differentiation block. We further show that NF-kappaB activity is upregulated in PAX7-FKHR cells when compared to parental MSCs due to upregulation of the PI3K/AKT pathway. In addition we show that NF-kappaB inhibits myogenesis via activation of cyclinD1/ cdk4 complexes, which sequester MyoD1, a key myogenic transcription factor. CONCLUSIONS: Our results highlight the importance of the NF-kappaB pathway in myogenesis and sarcomagenesis and suggest that this pathway may be one of the potential therapeutic targets in the treatment of ARMS.

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