PAX3-FOXO1A expression in rhabdomyosarcoma is driven by the targetable nuclear receptor NR4A1

Alexandra Lacey, Aline Rodrigues-Hoffman, Stephen Safe

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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-(phydroxy 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 b1-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. Ó2016 AACR.

Original languageEnglish (US)
Pages (from-to)732-741
Number of pages10
JournalCancer research
Volume77
Issue number3
DOIs
StatePublished - Feb 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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