Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target
Rhabdomyosarcoma (RMS) is definitely an aggressive pediatric soft tissue sarcoma. There’s two primary subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion-positive rhabdomyosarcoma, which expresses either PAX3-FOXO1 or PAX7-FOXO1 fusion proteins. There aren’t any targeted therapies for ARMS however, recent reports have started to illustrate the cooperation between epigenetic proteins and also the PAX3-FOXO1 fusion, indicating that epigenetic proteins is targets in ARMS. Here, we investigate contribution of BMI1, because of the established role of the epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient-derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC-209 and PTC-028) and located that this can lead to home loan business cell growth/rise in apoptosis in vitro, and delays tumor development in vivo. Our data claim that BMI1 inhibition activates the PTC-028 Hippo path via phosphorylation of LATS1/2 and subsequent decrease in YAP levels and YAP/TAZ target genes. These results identify BMI1 like a potential therapeutic vulnerability in ARMS and warrant further analysis of BMI1 in ARMS along with other sarcomas.