TY - JOUR
T1 - Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma
AU - Pomella, Silvia
AU - Sreenivas, Prethish
AU - Gryder, Berkley E.
AU - Wang, Long
AU - Milewski, David
AU - Cassandri, Matteo
AU - Baxi, Kunal
AU - Hensch, Nicole R.
AU - Carcarino, Elena
AU - Song, Young
AU - Chou, Hsien-Chao
AU - Yohe, Marielle E.
AU - Stanton, Benjamin Z.
AU - Amadio, Bruno
AU - Caruana, Ignazio
AU - De Stefanis, Cristiano
AU - De Vito, Rita
AU - Locatelli, Franco
AU - Chen, Yidong
AU - Chen, Eleanor Y.
AU - Houghton, Peter
AU - Khan, Javed
AU - Rota, Rossella
AU - Ignatius, Myron S.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - RHABDOMYOSARCOMA
KW - RHABDOMYOSARCOMA
UR - http://hdl.handle.net/10807/228261
U2 - 10.1038/s41467-020-20386-8
DO - 10.1038/s41467-020-20386-8
M3 - Article
SN - 2041-1723
VL - 12
SP - 1
EP - 15
JO - Nature Communications
JF - Nature Communications
ER -