PROX1 transcription factor is a master transcriptional regulator and essential for the stemness and growth of rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer in need of novel therapies. Here we show that the PROX1 transcription factor, which is essential for myoblast differentiation, is highly expressed in RMS tumors. We demonstrate that PROX1 regulates RMS cell proliferation, stemness and rhabdosphere formation in vitro and RMS tumor formation in mouse xenograft models. By using proximity labeling and mass spectrometry, we found that PROX1 interacts with the NuRD and CoREST (HDAC) complexes. PROX1 depletion reprogrammed the RMS transcriptome to resemble benign mesenchymal stem cells and repressed previously identified RMS effector transcripts, placing it upstream of these genes. Our studies reveal a major role of PROX1-HDAC interaction in RMS and give insights for novel therapeutic targets. RNA sequencing (RNA-seq) analysis of four biological replicates of PROX1 silenced (75% deletion) and control RD cells.