Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main 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 are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3-FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this 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 found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.

 

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Rhabdomyosarcoma (RMS) is an aggressive type of soft tissue sarcoma that primarily affects children. It is categorized into two main subtypes: alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS is further divided into fusion-positive rhabdomyosarcoma, which involves the expression of fusion proteins called PAX3-FOXO1 or PAX7-FOXO1.

Currently, there are no targeted therapies specifically designed for ARMS. However, recent studies have shed light on the potential role of epigenetic proteins in conjunction with the PAX3-FOXO1 fusion protein, suggesting that targeting these epigenetic regulators may be a viable approach for treating ARMS. In this context, the researchers investigated the involvement of BMI1, an epigenetic regulator known to sustain aggressiveness in various cancers.

The study found that BMI1 is expressed in ARMS tumors, patient-derived xenografts (PDXs), and cell lines. To explore the therapeutic potential of targeting BMI1, the researchers used RNA interference (RNAi) and two inhibitors called PTC-209 and PTC-028 to deplete BMI1. They observed that reducing BMI1 levels led to a decrease in cell growth and an increase in apoptosis (programmed cell death) in vitro (in cell cultures). Moreover, in vivo experiments using animal models showed that inhibiting BMI1 delayed tumor growth.

The results of the study suggest that inhibiting BMI1 activates the Hippo pathway, a signaling pathway involved in controlling cell growth and organ size. This activation occurs through the phosphorylation of LATS1/2, which subsequently leads to a reduction in YAP levels and the expression of YAP/TAZ target genes. The findings indicate that BMI1 inhibition could serve as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 as a target in ARMS and other sarcomas.

Overall, this study highlights the significance of BMI1 in ARMS and provides insights into its potential as a therapeutic target. Further research in this area may lead to the development of targeted therapies that can improve the outcomes for patients with ARMS and potentially other sarcomas as well.