Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma

Sci Transl Med. 2022 Jul 13;14(653):eabq2096. doi: 10.1126/scitranslmed.abq2096. Epub 2022 Jul 13.


Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1+ RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Child
  • Forkhead Box Protein O1 / metabolism
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • PAX3 Transcription Factor / genetics
  • PAX3 Transcription Factor / metabolism
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism
  • Paired Box Transcription Factors / therapeutic use
  • Rhabdomyosarcoma* / genetics
  • Rhabdomyosarcoma, Alveolar* / genetics
  • Rhabdomyosarcoma, Alveolar* / metabolism
  • Rhabdomyosarcoma, Alveolar* / pathology


  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Oncogene Proteins, Fusion
  • PAX3 Transcription Factor
  • PAX3 protein, human
  • Paired Box Transcription Factors
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4B protein, human