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The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

Targeted treatment for pediatric aRMS

Rhabdomyosarcoma is a soft tissue tumor in children that is difficult to treat. A chromosomal abnormality generates a fusion protein called PAX3:FOXO1 that drives chemoresistance and aggressive progression in patients with the alveolar subtype of the disease (aRMS). Early-phase clinical trials have shown tolerability of the histone deacetylase (HDAC) inhibitor entinostat in pediatric patients. Here, using cells and animal models, Bharathy et al. found that entinostat works in aRMS by specifically blocking the activity of HDAC3, thereby preventing epigenetic suppression of a microRNA that inhibits PAX3:FOXO1 translation. Without PAX3:FOXO1 protein, aRMS growth slowed, and tumors were sensitized to the chemotherapy vincristine. These findings and ongoing clinical trials show promise for an effective therapy for some patients with aRMS.

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