The Rna Helicase DDX5 Cooperates with EHMT2 to Sustain Alveolar Rhabdomyosarcoma Growth

Abstract

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood characterized by the inability to exit the proliferative myoblast-like stage. The alveolar fusion positive subtype (FP-ARMS) is the most aggressive and is mainly caused by the expression of PAX3/7-FOXO1 oncoproteins, which are challenging pharmacological targets. Here, we show that the DEAD box RNA helicase 5 (DDX5) is overexpressed in alveolar RMS cells and that its depletion and pharmacological inhibition decrease FP-ARMS viability and slow tumor growth in xenograft models. Mechanistically, we provide evidence that DDX5 functions upstream the EHMT2/AKT survival signalling pathway, by directly interacting with EHMT2mRNA and modulating its protein expression. We found that EHMT2 in turns regulates PAX3-FOXO1 activity in a methylation-dependent manner, thus sustaining FP-ARMS myoblastic state. Together, our findings identify a novel survival-promoting loop in FP-ARMS and highlight DDX5 as potential therapeutic target to arrest rhabdomyosarcoma growth.