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. SOURCE: Javed Khan (khanjav@mail.nih.gov) - Javed Khan NCI, NIH

Pluto Bioinformatics

GSE137168: Liaison between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion-Negative Rhabdomyosarcoma