Syndecan-4 affects myogenesis via Rac1-mediated actin remodeling and exhibits copy-number amplification and increased expression in human rhabdomyosarcoma tumors.

Abstract

Skeletal muscle demonstrates a high degree of regenerative capacity repeating the embryonic myogenic program under strict control. Rhabdomyosarcoma is the most common sarcoma in childhood and is characterized by impaired muscle differentiation. In this study, we observed that silencing the expression of syndecan-4, the ubiquitously expressed transmembrane heparan sulfate proteoglycan, significantly enhanced myoblast differentiation, and fusion. During muscle differentiation, the gradually decreasing expression of syndecan-4 allows the activation of Rac1, thereby mediating myoblast fusion. Single-molecule localized superresolution direct stochastic optical reconstruction microscopy (dSTORM) imaging revealed nanoscale changes in actin cytoskeletal architecture, and atomic force microscopy showed reduced elasticity of syndecan-4-knockdown cells during fusion. Syndecan-4 copy-number amplification was observed in 28% of human fusion-negative rhabdomyosarcoma tumors and was accompanied by increased syndecan-4 expression based on RNA sequencing data. Our study suggests that syndecan-4 can serve as a tumor driver gene in promoting rabdomyosarcoma tumor development. Our results contribute to the understanding of the role of syndecan-4 in skeletal muscle development, regeneration, and tumorigenesis.

• Authors: Kitti Szabo, Daniel Varga, Attila Gergely Vegh, Ning Liu, Xue Xiao, Lin Xu, Laszlo Dux, Miklos Erdelyi, Laszlo Rovo, Aniko Keller-Pinter
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 79 Issue 2 Pg. 122 (Feb 07 2022) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 35128576 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Actins
• RNA, Small Interfering
• Syndecan-4
• T-Lymphoma Invasion and Metastasis-inducing Protein 1
• rac1 GTP-Binding Protein

Topics

• Actin Cytoskeleton
• Actins (metabolism)
• Animals
• Cell Differentiation
• Cell Line
• DNA Copy Number Variations
• Humans
• Male
• Mice
• Muscle Development
• Muscle, Skeletal (metabolism)
• Myoblasts (cytology, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Rats
• Rats, Wistar
• Rhabdomyosarcoma (metabolism, pathology)
• Syndecan-4 (antagonists & inhibitors, genetics, metabolism)
• T-Lymphoma Invasion and Metastasis-inducing Protein 1 (metabolism)
• rac1 GTP-Binding Protein (metabolism)