Project description:Rhabdomyosarcoma (RMS) is a pediatric malignancy of mesenchymal origin. Fusion Negative-RMS (FN-RMS) tumors are associated with RAS-pathway activation. RMS tumors express pro-differentiation myogenic transcription factors MYOD and MYOG, yet why they are unable to differentiate is poorly understood. Here we show that SNAI2 is highly expressed in FN-RMS, is regulated by MYOD and blocks myogenic differentiation promoting growth. Molecularly, SNAI2 preferentially binds E-Box-associated enhancer elements and represses expression by dampening enhancer function. SNAI2 inhibits MYOD at a subset of myogenic enhancers associated with terminal differentiation. Functional dissection demonstrates SNAI2 suppresses a MYOG, MEF2 and CDKN1A differentiation program. SNAI2 knockdown transcriptionally mimics a chemical blockade of the mutant RAS signal in FN-RMS, providing new insight connecting the genetic and epigenetic causes of this disease.
Project description:Trametinib-treated rhabdomyosarcoma cells undergo transcriptional reprogramming akin to myogenic differentiation. This reprogramming is induced by loss of ERK-mediated inhibition of MYOG expression. Restoration of MYOG allows establishment of super-enhancers at genes expressed by terminally differentiated myotubes. Our findings demonstrate that aberrant MAP kinase activity blocks differentiation in rhabdomyosarcoma and highlight trametinib as a potential therapeutic for RAS-mutated rhabdomyosarcoma.
Project description:Trametinib-treated rhabdomyosarcoma cells undergo transcriptional reprogramming akin to myogenic differentiation. This reprogramming is induced by loss of ERK-mediated inhibition of MYOG expression. Restoration of MYOG allows establishment of super-enhancers at genes expressed by terminally differentiated myotubes. Our findings demonstrate that aberrant MAP kinase activity blocks differentiation in rhabdomyosarcoma and highlight trametinib as a potential therapeutic for RAS-mutated rhabdomyosarcoma.
