CASZ1 induces skeletal muscle and rhabdomyosarcoma differentiation through a feed-forward loop with MYOD and MYOG

Nat Commun. 2020 Feb 14;11(1):911. doi: 10.1038/s41467-020-14684-4.


Embryonal rhabdomyosarcoma (ERMS) is a childhood cancer that expresses myogenic master regulatory factor MYOD but fails to differentiate. Here, we show that the zinc finger transcription factor CASZ1 up-regulates MYOD signature genes and induces skeletal muscle differentiation in normal myoblasts and ERMS. The oncogenic activation of the RAS-MEK pathway suppresses CASZ1 expression in ERMS. ChIP-seq, ATAC-seq and RNA-seq experiments reveal that CASZ1 directly up-regulates skeletal muscle genes and represses non-muscle genes through affecting regional epigenetic modifications, chromatin accessibility and super-enhancer establishment. Next generation sequencing of primary RMS tumors identified a single nucleotide variant in the CASZ1 coding region that potentially contributes to ERMS tumorigenesis. Taken together, loss of CASZ1 activity, due to RAS-MEK signaling or genetic alteration, impairs ERMS differentiation, contributing to RMS tumorigenesis.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Carcinogenesis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, SCID
  • Muscle Development*
  • Muscle, Skeletal / metabolism*
  • MyoD Protein / genetics
  • MyoD Protein / metabolism*
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • Myogenin / genetics
  • Myogenin / metabolism*
  • Rhabdomyosarcoma, Embryonal / genetics
  • Rhabdomyosarcoma, Embryonal / metabolism*
  • Rhabdomyosarcoma, Embryonal / physiopathology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • CASZ1 protein, human
  • DNA-Binding Proteins
  • MYOG protein, human
  • MyoD Protein
  • Myogenin
  • Transcription Factors