A dysfunctional miR-1-TRPS1-MYOG axis drives ERMS by suppressing terminal myogenic differentiation

• Published in: Molecular therapy Vol. 31; no. 9; pp. 2612 - 2632
• Main Authors: Hüttner, Sören S., Henze, Henriette, Elster, Dana, Koch, Philipp, Anderer, Ursula, von Eyss, Björn, von Maltzahn, Julia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.09.2023; American Society of Gene & Cell Therapy
• Subjects: Cell Differentiation - genetics; Cell Line, Tumor; Child; ERMS; Humans; MicroRNAs - genetics; miRNA; Muscle Development - genetics; muscle stem cell; myogenic differentiation; Myogenin - genetics; Myogenin - metabolism; Original; RD cells; regeneration; Repressor Proteins; rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal - genetics; Rhabdomyosarcoma, Embryonal - metabolism; Rhabdomyosarcoma, Embryonal - pathology; skeletal muscle; TRPS1; ERMS; regeneration; TRPS1; myogenic differentiation; RD cells; miRNA; rhabdomyosarcoma; skeletal muscle; muscle stem cell
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2023.07.003

Rhabdomyosarcoma is the most common pediatric soft tissue tumor, comprising two major subtypes: the PAX3/7-FOXO1 fusion-negative embryonal and the PAX3/7-FOXO1 fusion-positive alveolar subtype. Here, we demonstrate that the expression levels of the transcriptional repressor TRPS1 are specifically enhanced in the embryonal subtype, resulting in impaired terminal myogenic differentiation and tumor growth. During normal myogenesis, expression levels of TRPS1 have to decrease to allow myogenic progression, as demonstrated by overexpression of TRPS1 in myoblasts impairing myotube formation. Consequentially, myogenic differentiation in embryonal rhabdomyosarcoma in vitro as well as in vivo can be achieved by reducing TRPS1 levels. Furthermore, we show that TRPS1 levels in RD cells, the bona fide model cell line for embryonal rhabdomyosarcoma, are regulated by miR-1 and that TRPS1 and MYOD1 share common genomic binding sites. The myogenin (MYOG) promoter is one of the critical targets of TRPS1 and MYOD1; we demonstrate that TRPS1 restricts MYOG expression and thereby inhibits terminal myogenic differentiation. Therefore, reduction of TRPS1 levels in embryonal rhabdomyosarcoma might be a therapeutic approach to drive embryonal rhabdomyosarcoma cells into myogenic differentiation, thereby generating postmitotic myotubes. [Display omitted] Expression levels of the transcriptional repressor TRPS1 are specifically enhanced in embryonal rhabdomyosarcoma, resulting in impaired terminal myogenic differentiation by restricting MYOGENIN expression and tumor growth. However, myogenic differentiation in embryonal rhabdomyosarcoma can be achieved by reducing TRPS1 levels, offering a new therapeutic approach for embryonal rhabdomyosarcoma.