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. Chen; Peter Houghton; Javed Khan; Rossella Rota; Myron S. Ignatius

doi:10.1038/s41467-020-20386-8

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

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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.

Original language	English (US)
Article number	192
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20386-8
State	Published - Dec 1 2021

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Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Pomella, S., Sreenivas, P., Gryder, B. E., Wang, L., Milewski, D., Cassandri, M., Baxi, K., Hensch, N. R., Carcarino, E., Song, Y., Chou, H. C., Yohe, M. E., Stanton, B. Z., Amadio, B., Caruana, I., De Stefanis, C., De Vito, R., Locatelli, F., Chen, Y., ... Ignatius, M. S. (2021). Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma. Nature communications, 12(1), [192]. https://doi.org/10.1038/s41467-020-20386-8

Pomella, S, Sreenivas, P, Gryder, BE, Wang, L, Milewski, D, Cassandri, M, Baxi, K, Hensch, NR, Carcarino, E, Song, Y, Chou, HC, Yohe, ME, Stanton, BZ, Amadio, B, Caruana, I, De Stefanis, C, De Vito, R, Locatelli, F, Chen, Y, Chen, EY, Houghton, P, Khan, J, Rota, R & Ignatius, MS 2021, 'Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma', Nature communications, vol. 12, no. 1, 192. https://doi.org/10.1038/s41467-020-20386-8

@article{f6eaecaffadc4527bba69f67034087b5,

title = "Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma",

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.",

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

note = "Funding Information: The Myogenin (Wright WE) and MHC (Fishman DA) antibodies were obtained from the Developmental Studies Hybridoma Bank, developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA 52242, USA. Grant Support: This project has been funded with federal funds from NIH grants MI and PH (R00CA175184, NCI P01 CA165995), CPRIT grant (RR160062) to MI, Associazione Italiana Ricerca sul Cancro (AIRC 15312) and Italian Ministry of Health (PE-2013-02355271) to RR, AIRC 5xmille (9962) to FL. S. Pomella is a recipient of a Fondazione Veronesi fellowship. MI is a recipient of the Max and Minnie Tomerlin Volker fund young investigator award. Kunal Baxi is a T32/TL1 fellow (CA148724) and (TL1TR002647). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-020-20386-8",

language = "English (US)",

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journal = "Nature Communications",

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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.

N1 - Funding Information: The Myogenin (Wright WE) and MHC (Fishman DA) antibodies were obtained from the Developmental Studies Hybridoma Bank, developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA 52242, USA. Grant Support: This project has been funded with federal funds from NIH grants MI and PH (R00CA175184, NCI P01 CA165995), CPRIT grant (RR160062) to MI, Associazione Italiana Ricerca sul Cancro (AIRC 15312) and Italian Ministry of Health (PE-2013-02355271) to RR, AIRC 5xmille (9962) to FL. S. Pomella is a recipient of a Fondazione Veronesi fellowship. MI is a recipient of the Max and Minnie Tomerlin Volker fund young investigator award. Kunal Baxi is a T32/TL1 fellow (CA148724) and (TL1TR002647). Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

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.

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AN - SCOPUS:85098964586

SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

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ER -

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

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