P-cadherin is a direct PAX3-FOXO1A target involved in alveolar rhabdomyosarcoma aggressiveness

Oncogene. 2013 Apr 11;32(15):1876-87. doi: 10.1038/onc.2012.217. Epub 2012 Jun 18.


Alveolar rhabdomyosarcoma (ARMS) is an aggressive childhood cancer of striated muscle characterized by the presence of the PAX3-FOXO1A or PAX7-FOXO1A chimeric oncogenic transcription factor. Identification of their targets is essential for understanding ARMS pathogenesis. To this aim, we analyzed transcriptomic data from rhabdomyosarcoma samples and found that P-cadherin expression is correlated with PAX3/7-FOXO1A presence. We then show that expression of a PAX3 dominant negative variant inhibits P-cadherin expression in ARMS cells. Using mouse models carrying modified Pax3 alleles, we demonstrate that P-cadherin is expressed in the dermomyotome and lies genetically downstream from the myogenic factor Pax3. Moreover, in vitro gel shift analysis and chromatin immunoprecipitation indicate that the P-cadherin gene is a direct transcriptional target for PAX3/7-FOXO1A. Finally, P-cadherin expression in normal myoblasts inhibits myogenesis and induces myoblast transformation, migration and invasion. Conversely, P-cadherin downregulation by small hairpin RNA decreases the transformation, migration and invasive potential of ARMS cells. P-cadherin also favors cadherin switching, which is a hallmark of metastatic progression, by controlling N- and M-cadherin expression and/or localization. Our findings demonstrate that P-cadherin is a direct PAX3-FOXO1A transcriptional target involved in ARMS aggressiveness. Therefore, P-cadherin emerges as a new and attractive target for therapeutic intervention in ARMS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Movement / genetics
  • Cell Transformation, Neoplastic / genetics
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Transgenic
  • Neoplasm Invasiveness / genetics
  • PAX3 Transcription Factor
  • PAX7 Transcription Factor / metabolism
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Rhabdomyosarcoma, Alveolar / metabolism*
  • Rhabdomyosarcoma, Alveolar / pathology
  • Sequence Alignment
  • Transcription, Genetic


  • Cadherins
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • PAX3 Transcription Factor
  • PAX7 Transcription Factor
  • Paired Box Transcription Factors
  • Pax7 protein, mouse
  • RNA, Small Interfering
  • Pax3 protein, mouse