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 Stefanis, Rita Vito, Franco Locatelli, Yidong Chen, Eleanor Y. Chen, Peter Houghton, Javed Khan (), Rossella Rota () and Myron S. Ignatius ()
Additional contact information
Silvia Pomella: Bambino Gesù Children’s Hospital, IRCCS
Prethish Sreenivas: University of Texas Health Sciences Center
Berkley E. Gryder: Genetics Branch, NCI, NIH
Long Wang: University of Texas Health Sciences Center
David Milewski: Genetics Branch, NCI, NIH
Matteo Cassandri: Bambino Gesù Children’s Hospital, IRCCS
Kunal Baxi: University of Texas Health Sciences Center
Nicole R. Hensch: University of Texas Health Sciences Center
Elena Carcarino: Bambino Gesù Children’s Hospital, IRCCS
Young Song: Genetics Branch, NCI, NIH
Hsien-Chao Chou: Genetics Branch, NCI, NIH
Marielle E. Yohe: Genetics Branch, NCI, NIH
Benjamin Z. Stanton: The Ohio State University
Bruno Amadio: SAFU Laboratory, Translational Research Area, Regina Elena National Cancer Institute
Ignazio Caruana: Bambino Gesù Children’s Hospital, IRCCS
Cristiano Stefanis: Histology-Core Facility, Bambino Gesu’ Children’s Hospital, IRCCS
Rita Vito: Bambino Gesu’ Children’s Hospital, IRCCS
Franco Locatelli: Bambino Gesù Children’s Hospital, IRCCS
Yidong Chen: University of Texas Health Sciences Center
Eleanor Y. Chen: University of Washington
Peter Houghton: University of Texas Health Sciences Center
Javed Khan: Genetics Branch, NCI, NIH
Rossella Rota: Bambino Gesù Children’s Hospital, IRCCS
Myron S. Ignatius: University of Texas Health Sciences Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20386-8

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