TAK1 is a key regulator of oncogenic signaling and differentiation blockade in rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is a malignant soft tissue sarcoma with a skeletal muscle phenotype, accounting for approximately 50% of all pediatric soft tissue sarcomas and 8% of all childhood cancers. Although RMS cells express myogenic regulatory factors, they fail to undergo terminal differentiation into mature muscle cells. Transforming growth factor {beta}-activated kinase 1 (TAK1) is a major signaling protein that activates multiple intracellular pathways in response to growth factors, cytokines, and microbial products. Emerging evidence suggests that TAK1 is also an important regulator of self-renewal, proliferation, and differentiation of muscle progenitor cells. However, the role and mechanisms of action of TAK1 in RMS remain completely unknown. In this study, we demonstrate that TAK1 expression and activity are markedly elevated in a panel of RMS cell lines and in patient tumor specimens. Reverse phase protein array (RPPA) analyses revealed that TAK1 regulates the expression and activity of many molecules involved in cell cycle control, cell proliferation, and oncogenic signaling. Genetic knockdown or pharmacological inhibition of TAK1 suppresses RMS cell proliferation, migration, and invasiveness, while also promoting terminal myogenic differentiation. TAK1 inhibits differentiation in RMS, at least in part, through up-regulating YAP1 signaling. Our results also demonstrate that inducible knockdown of TAK1 in human RMS xenografts retards tumor growth and enhances myogenic differentiation in vivo. Collectively, these findings uncover a previously unrecognized role for TAK1 in RMS growth and differentiation, and suggest that TAK1 can be a potential therapeutic target for the treatment of RMS.