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

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

Author information

1
Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
3
Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
4
Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
5
Research Center, Shriners Hospital for Children, Portland, OR 97239, USA.
6
Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA.
7
Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229, USA.
8
Department of Pediatric Hematology Oncology and Blood and Marrow Transplantation, Cleveland Clinic Children's, Cleveland, OH 44195, USA.
9
Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
10
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21224, USA.
11
Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
12
Electrical and Computer Engineering, Texas Tech University, Lubbock, TX 79409, USA.
13
Champions Oncology, Rockville, MD 20850, USA.
14
Syndax Pharmaceuticals, Waltham, MA 02451, USA.
15
The Jackson Laboratory, Sacramento, CA 95838, USA.
16
Seattle Children's Hospital, Seattle, WA 98105, USA.
17
Cancer Molecular Pathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892-1500, USA.
18
Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA.
19
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
20
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada.
21
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa K1H 8M5, Canada.
22
Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA. charles@cc-tdi.org.

Abstract

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.

PMID:
30459282
DOI:
10.1126/scisignal.aau7632

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