Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma

Silvia Pomella, Prethish Sreenivas, Berkley E. Gryder, Long Wang, David Milewski, Matteo Cassandri, Kunal Baxi, Nicole R. Hensch, Elena Carcarino, Young Song, Hsien Chao Chou, Marielle E. Yohe, Benjamin Z. Stanton, Bruno Amadio, Ignazio Caruana, Cristiano De Stefanis, Rita De Vito, Franco Locatelli, Yidong Chen, Eleanor Y. ChenPeter Houghton, Javed Khan, Rossella Rota, Myron S. Ignatius

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Rhabdomyosarcoma (RMS) is an aggressive pediatric malignancy of the muscle, that includes Fusion Positive (FP)-RMS harboring PAX3/7-FOXO1 and Fusion Negative (FN)-RMS commonly with RAS pathway mutations. RMS express myogenic master transcription factors MYOD and MYOG yet are unable to terminally differentiate. Here, we report that SNAI2 is highly expressed in FN-RMS, is oncogenic, blocks myogenic differentiation, and promotes growth. MYOD activates SNAI2 transcription via super enhancers with striped 3D contact architecture. Genome wide chromatin binding analysis demonstrates that SNAI2 preferentially binds enhancer elements and competes with MYOD at a subset of myogenic enhancers required for terminal differentiation. SNAI2 also suppresses expression of a muscle differentiation program modulated by MYOG, MEF2, and CDKN1A. Further, RAS/MEK-signaling modulates SNAI2 levels and binding to chromatin, suggesting that the differentiation blockade by oncogenic RAS is mediated in part by SNAI2. Thus, an interplay between SNAI2, MYOD, and RAS prevents myogenic differentiation and promotes tumorigenesis.

Original languageEnglish (US)
Article number192
JournalNature communications
Issue number1
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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