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NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth

BAF chromatin remodeling complexes play important roles in chromatin regulation and cancer. Here, we report that Ewing sarcoma cells are dependent on the autocrine signaling mediated by NELL2, a secreted glycoprotein that has been characterized as an axon guidance molecule. NELL2 uses Robo3 as the r...

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Autores principales: Jayabal, Panneerselvam, Zhou, Fuchun, Lei, Xiufen, Ma, Xiuye, Blackman, Barron, Weintraub, Susan T., Houghton, Peter J., Shiio, Yuzuru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312579/
https://www.ncbi.nlm.nih.gov/pubmed/34233189
http://dx.doi.org/10.1016/j.celrep.2021.109254
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author Jayabal, Panneerselvam
Zhou, Fuchun
Lei, Xiufen
Ma, Xiuye
Blackman, Barron
Weintraub, Susan T.
Houghton, Peter J.
Shiio, Yuzuru
author_facet Jayabal, Panneerselvam
Zhou, Fuchun
Lei, Xiufen
Ma, Xiuye
Blackman, Barron
Weintraub, Susan T.
Houghton, Peter J.
Shiio, Yuzuru
author_sort Jayabal, Panneerselvam
collection PubMed
description BAF chromatin remodeling complexes play important roles in chromatin regulation and cancer. Here, we report that Ewing sarcoma cells are dependent on the autocrine signaling mediated by NELL2, a secreted glycoprotein that has been characterized as an axon guidance molecule. NELL2 uses Robo3 as the receptor to transmit critical growth signaling. NELL2 signaling inhibits cdc42 and upregulates BAF complexes and EWS-FLI1 transcriptional output. We demonstrate that cdc42 is a negative regulator of BAF complexes, inducing actin polymerization and complex disassembly. Furthermore, we identify NELL2(high)CD133(high)EWS-FLI1(high) and NELL2(low)CD133(low)EWS-FLI1(low) populations in Ewing sarcoma, which display phenotypes consistent with high and low NELL2 signaling, respectively. We show that NELL2, CD133, and EWS-FLI1 positively regulate each other and upregulate BAF complexes and cell proliferation in Ewing sarcoma. These results reveal a signaling pathway regulating critical chromatin remodeling complexes and cancer cell proliferation.
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spelling pubmed-83125792021-07-26 NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth Jayabal, Panneerselvam Zhou, Fuchun Lei, Xiufen Ma, Xiuye Blackman, Barron Weintraub, Susan T. Houghton, Peter J. Shiio, Yuzuru Cell Rep Article BAF chromatin remodeling complexes play important roles in chromatin regulation and cancer. Here, we report that Ewing sarcoma cells are dependent on the autocrine signaling mediated by NELL2, a secreted glycoprotein that has been characterized as an axon guidance molecule. NELL2 uses Robo3 as the receptor to transmit critical growth signaling. NELL2 signaling inhibits cdc42 and upregulates BAF complexes and EWS-FLI1 transcriptional output. We demonstrate that cdc42 is a negative regulator of BAF complexes, inducing actin polymerization and complex disassembly. Furthermore, we identify NELL2(high)CD133(high)EWS-FLI1(high) and NELL2(low)CD133(low)EWS-FLI1(low) populations in Ewing sarcoma, which display phenotypes consistent with high and low NELL2 signaling, respectively. We show that NELL2, CD133, and EWS-FLI1 positively regulate each other and upregulate BAF complexes and cell proliferation in Ewing sarcoma. These results reveal a signaling pathway regulating critical chromatin remodeling complexes and cancer cell proliferation. 2021-07-06 /pmc/articles/PMC8312579/ /pubmed/34233189 http://dx.doi.org/10.1016/j.celrep.2021.109254 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Jayabal, Panneerselvam
Zhou, Fuchun
Lei, Xiufen
Ma, Xiuye
Blackman, Barron
Weintraub, Susan T.
Houghton, Peter J.
Shiio, Yuzuru
NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth
title NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth
title_full NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth
title_fullStr NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth
title_full_unstemmed NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth
title_short NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth
title_sort nell2-cdc42 signaling regulates baf complexes and ewing sarcoma cell growth
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312579/
https://www.ncbi.nlm.nih.gov/pubmed/34233189
http://dx.doi.org/10.1016/j.celrep.2021.109254
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