Journal Article

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

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

2021

Overview

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. Rhabdomyosarcomas are tumours blocked in myogenic differentiation, which despite the expression of master muscle regulatory factors, including MYOD, are unable to differentiate. Here, the authors show that SNAI2 is upregulated by MYOD through super enhancers, binds to MYOD target enhancers, and arrests differentiation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 14/19 / 38 / 38/23 / 38/91 / 45/15 / 45/23 / 45/29 / 45/41 / 45/88 / 45/90 / 631/67 / 631/67/1798 / 631/67/2332 / 631/67/395 / 631/67/69 / 82/51 / Animals / Binding / Cancer / Carcinogenesis - genetics / Carcinogenesis - metabolism / Cell Differentiation - genetics / Cell Line, Tumor / Chromatin / Cyclin-Dependent Kinase Inhibitor p21 - metabolism / Differentiation / Enhancers / Female / FOXO1 protein / Gene expression / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Gene loci / Genomes / Heterografts / Hospitals / Humanities and Social Sciences / Humans / Laboratories / Male / Malignancy / Medical research / MEF2 Transcription Factors - metabolism / Mice / Mice, SCID / multidisciplinary / Muscle Development - genetics / Muscles / Mutation / Myocyte enhancer factor 2 / MyoD protein / MyoD Protein - genetics / MyoD Protein - metabolism / Myogenin - metabolism / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Oncogenes / Pax3 protein / Pediatrics / Proteins / Rhabdomyosarcoma / Rhabdomyosarcoma - genetics / Rhabdomyosarcoma - metabolism / Rhabdomyosarcoma - pathology / Rhabdomyosarcoma, Alveolar - genetics / Rhabdomyosarcoma, Embryonal - genetics / Science / Science (multidisciplinary) / Snail Family Transcription Factors - genetics / Snail Family Transcription Factors - metabolism / Snail protein / Transcription factors / Transcriptome / Tumorigenesis / Tumors