title: PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1.
abstract: Alveolar rhabdomyosarcoma (ARMS) is a devastating pediatric disease driven by expression of the oncogenic fusion gene PAX3-FOXO1A. In this study, we report overexpression of the nuclear receptor NR4A1 in rhabdomyosarcomas that is sufficient to drive high expression of PAX3-FOXO1A there. RNAi-mediated silencing of NR4A1 decreased expression of PAX3-FOXO1A and its downstream effector genes. Similarly, cell treatment with the NR4A1 small-molecule antagonists 1,1-bis(3-indolyl)-1-(p-hydroxy or p-carbomethoxyphenyl)methane (C-DIM) decreased PAX3-FOXO1A. Mechanistic investigations revealed a requirement for the NR4A1/Sp4 complex to bind GC-rich promoter regions to elevate transcription of the PAX3-FOXO1A gene. In parallel, NR4A1 also regulated expression of β1-integrin, which with PAX3-FOXO1A, contributed to tumor cell migration that was blocked by C-DIM/NR4A1 antagonists. Taken together, our results provide a preclinical rationale for the use of NR4A1 small-molecule antagonists to treat ARMS and other rhabdomyosarcomas driven by PAX3-FOXO1A. Cancer Res; 77(3); 732-41. ©2016 AACR.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lacey
authors.affiliation: Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas.
authors.forename: Aline
authors.initials: A
authors.lastname: Rodrigues-Hoffman
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas. ssafe@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis*; D051761:Paired Box Transcription Factors / Q000096:biosynthesis*; D011897:Random Allocation; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D015514:Oncogene Proteins, Fusion; C471563:PAX3-FOXO1A fusion protein, human; D051761:Paired Box Transcription Factors