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

Author

Listed:
  • Silvia Pomella

    (Bambino Gesù Children’s Hospital, IRCCS
    Genetics Branch, NCI, NIH)

  • 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
    Pediatric Oncology 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
    Sapienza University of Rome)

  • 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)

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.

Suggested Citation

  • 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. Y, 2021. "Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20386-8
    DOI: 10.1038/s41467-020-20386-8
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    Cited by:

    1. Silvia Pomella & Matteo Cassandri & Lucrezia D’Archivio & Antonella Porrazzo & Cristina Cossetti & Doris Phelps & Clara Perrone & Michele Pezzella & Antonella Cardinale & Marco Wachtel & Sara Aloisi &, 2023. "MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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