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

Sci Signal. 2018 Nov 20;11(557):eaau7632. doi: 10.1126/scisignal.aau7632.


Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3-SMARCA4-miR-27a-PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Computational Biology
  • DNA Helicases / metabolism*
  • Drug Resistance, Neoplasm
  • Epigenesis, Genetic
  • Female
  • Fluorescence Resonance Energy Transfer
  • Forkhead Box Protein O1 / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Mice
  • MicroRNAs / metabolism*
  • Neoplasm Transplantation
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins, Fusion / metabolism*
  • PAX3 Transcription Factor / metabolism
  • Paired Box Transcription Factors / metabolism*
  • Pyridines / pharmacology
  • Rhabdomyosarcoma, Alveolar / metabolism*
  • Sequence Analysis, RNA
  • Transcription Factors / metabolism*
  • Vincristine / pharmacology


  • Antineoplastic Agents
  • Benzamides
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Histone Deacetylase Inhibitors
  • MIRN27 microRNA, human
  • MicroRNAs
  • Mirn27 microRNA, mouse
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • PAX3 Transcription Factor
  • PAX3-FOXO1A fusion protein, human
  • PAX3-FOXO1A fusion protein, mouse
  • Paired Box Transcription Factors
  • Pyridines
  • Transcription Factors
  • Pax3 protein, mouse
  • entinostat
  • Vincristine
  • Histone Deacetylases
  • histone deacetylase 3
  • SMARCA4 protein, human
  • Smarca4 protein, mouse
  • DNA Helicases