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The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma.
Bharathy, Narendra; Berlow, Noah E; Wang, Eric; Abraham, Jinu; Settelmeyer, Teagan P; Hooper, Jody E; Svalina, Matthew N; Ishikawa, Yoshihiro; Zientek, Keith; Bajwa, Zia; Goros, Martin W; Hernandez, Brian S; Wolff, Johannes E; Rudek, Michelle A; Xu, Linping; Anders, Nicole M; Pal, Ranadip; Harrold, Alexandria P; Davies, Angela M; Ashok, Arya; Bushby, Darnell; Mancini, Maria; Noakes, Christopher; Goodwin, Neal C; Ordentlich, Peter; Keck, James; Hawkins, Douglas S; Rudzinski, Erin R; Chatterjee, Bishwanath; Bächinger, Hans Peter; Barr, Frederic G; Liddle, Jennifer; Garcia, Benjamin A; Mansoor, Atiya; Perkins, Theodore J; Vakoc, Christopher R; Michalek, Joel E; Keller, Charles.
Afiliação
  • Bharathy N; Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA.
  • Berlow NE; Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA.
  • Wang E; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • Abraham J; Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
  • Settelmeyer TP; Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA.
  • Hooper JE; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
  • Svalina MN; Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA.
  • Ishikawa Y; Research Center, Shriners Hospital for Children, Portland, OR 97239, USA.
  • Zientek K; Research Center, Shriners Hospital for Children, Portland, OR 97239, USA.
  • Bajwa Z; Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA.
  • Goros MW; Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA.
  • Hernandez BS; Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229, USA.
  • Wolff JE; Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229, USA.
  • Rudek MA; Department of Pediatric Hematology Oncology and Blood and Marrow Transplantation, Cleveland Clinic Children's, Cleveland, OH 44195, USA.
  • Xu L; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
  • Anders NM; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21224, USA.
  • Pal R; Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
  • Harrold AP; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
  • Davies AM; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21224, USA.
  • Ashok A; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
  • Bushby D; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21224, USA.
  • Mancini M; Electrical and Computer Engineering, Texas Tech University, Lubbock, TX 79409, USA.
  • Noakes C; Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA.
  • Goodwin NC; Champions Oncology, Rockville, MD 20850, USA.
  • Ordentlich P; Champions Oncology, Rockville, MD 20850, USA.
  • Keck J; Champions Oncology, Rockville, MD 20850, USA.
  • Hawkins DS; Champions Oncology, Rockville, MD 20850, USA.
  • Rudzinski ER; Champions Oncology, Rockville, MD 20850, USA.
  • Chatterjee B; Champions Oncology, Rockville, MD 20850, USA.
  • Bächinger HP; Syndax Pharmaceuticals, Waltham, MA 02451, USA.
  • Barr FG; The Jackson Laboratory, Sacramento, CA 95838, USA.
  • Liddle J; Seattle Children's Hospital, Seattle, WA 98105, USA.
  • Garcia BA; Seattle Children's Hospital, Seattle, WA 98105, USA.
  • Mansoor A; Cancer Molecular Pathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892-1500, USA.
  • Perkins TJ; Research Center, Shriners Hospital for Children, Portland, OR 97239, USA.
  • Vakoc CR; Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA.
  • Michalek JE; Cancer Molecular Pathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892-1500, USA.
  • Keller C; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Signal ; 11(557)2018 11 20.
Article em En | MEDLINE | ID: mdl-30459282
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 PAX3FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3FOXO1 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 PAX3FOXO1 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 PAX3FOXO1 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-PAX3FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas Nucleares / Proteínas de Fusão Oncogênica / Rabdomiossarcoma Alveolar / DNA Helicases / MicroRNAs / Fatores de Transcrição Box Pareados / Inibidores de Histona Desacetilases / Histona Desacetilases Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas Nucleares / Proteínas de Fusão Oncogênica / Rabdomiossarcoma Alveolar / DNA Helicases / MicroRNAs / Fatores de Transcrição Box Pareados / Inibidores de Histona Desacetilases / Histona Desacetilases Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article