TY - JOUR
T1 - SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry
AU - Decaesteker, Bieke
AU - Louwagie, Amber
AU - Loontiens, Siebe
AU - de Vloed, Fanny
AU - Bekaert, Sarah-Lee
AU - Roels, Juliette
AU - Vanhauwaert, Suzanne
AU - de Brouwer, Sara
AU - Sanders, Ellen
AU - Berezovskaya, Alla
AU - Denecker, Geertrui
AU - D'haene, Eva
AU - van Haver, Stéphane
AU - van Loocke, Wouter
AU - van Dorpe, Jo
AU - Creytens, David
AU - van Roy, Nadine
AU - Pieters, Tim
AU - van Neste, Christophe
AU - Fischer, Matthias
AU - van Vlierberghe, Pieter
AU - Roberts, Stephen S.
AU - Schulte, Johannes
AU - Ek, Sara
AU - Versteeg, Rogier
AU - Koster, Jan
AU - van Nes, Johan
AU - Zimmerman, Mark
AU - de Preter, Katleen
AU - Speleman, Frank
N1 - Funding Information: The authors would like to thank C. Nunes, L. Mus, K. Verboom, S. Claeys, J. Van Laere and E. De Smet for technical assistance, P. Reynolds and M. Hogarty for providing the COG-N-373 cell line. We acknowledge the use of the Integrated Genomics Operation Core, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. This research was supported by the following funding agencies: the Belgian Foundation against Cancer (project 2015-146 and F/2018/1246) to F.S., Ghent University (BOF10/GOA/019, BOF16/GOA/23 and BOF/24 J/2021/150) to F.S., the Belgian Program of Interuniversity Poles of Attraction (IUAP Phase VII - P7/03) to F.S., the Fund for Scientific Research Flanders (Research projects G053012N, G050712N and G051516N to F.S., G021415N to K.D and F.S.), ‘Kom op tegen Kanker’ (Stand up to Cancer) the Flemish cancer society (Research grant to F.S.), the European Union H2020 (OPTIMIZE-NB GOD9415N and TRANSCAN-ON THE TRAC GOD8815N to F.S.) and FP7 (ENCCA 261474 and ASSET 259348 to F.S.), ‘Kinderkankerfonds’ (Research grant to F.S.), Olivia Fund to F.S. and Villa Joep to F.S. The following authors B.D., A.L., and S.V. were supported by an FWO grant (FWO3F02013001701/02, FWO.3F0.2019.0033.01, and FWO.3F0.2019.0041.01 respectively). B.D. was supported by CRIG (E/02578/01). A.L. was supported by Kom op tegen Kanker (STI.VLK.2018.0016.01). M.W.Z. was supported by grants from the Alex’s Lemonade Stand Foundation, Charles A. King Trust, and Claudia Adams Barr Foundation. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. Here, we identify SOX11 as a dependency transcription factor in adrenergic neuroblastoma based on recurrent chromosome 2p focal gains and amplifications, specific expression in the normal sympatho-adrenal lineage and adrenergic neuroblastoma, regulation by multiple adrenergic specific (super-)enhancers and strong dependency on high SOX11 expression in adrenergic neuroblastomas. SOX11 regulated direct targets include genes implicated in epigenetic control, cytoskeleton and neurodevelopment. Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A. Additionally, the histone deacetylase HDAC2, PRC1 complex component CBX2, chromatin-modifying enzyme KDM1A/LSD1 and pioneer factor c-MYB are regulated by SOX11. Finally, SOX11 is identified as a core transcription factor of the core regulatory circuitry (CRC) in adrenergic high-risk neuroblastoma with a potential role as epigenetic master regulator upstream of the CRC.
AB - The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. Here, we identify SOX11 as a dependency transcription factor in adrenergic neuroblastoma based on recurrent chromosome 2p focal gains and amplifications, specific expression in the normal sympatho-adrenal lineage and adrenergic neuroblastoma, regulation by multiple adrenergic specific (super-)enhancers and strong dependency on high SOX11 expression in adrenergic neuroblastomas. SOX11 regulated direct targets include genes implicated in epigenetic control, cytoskeleton and neurodevelopment. Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A. Additionally, the histone deacetylase HDAC2, PRC1 complex component CBX2, chromatin-modifying enzyme KDM1A/LSD1 and pioneer factor c-MYB are regulated by SOX11. Finally, SOX11 is identified as a core transcription factor of the core regulatory circuitry (CRC) in adrenergic high-risk neuroblastoma with a potential role as epigenetic master regulator upstream of the CRC.
UR - http://www.scopus.com/inward/record.url?scp=85149544273&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-36735-2
DO - https://doi.org/10.1038/s41467-023-36735-2
M3 - Article
C2 - 36882421
SN - 2041-1723
VL - 14
SP - 1267
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1267
ER -