TY - JOUR
T1 - TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets
AU - Decaesteker, Bieke
AU - Denecker, Geertrui
AU - Van Neste, Christophe
AU - Dolman, Emmy M.
AU - Van Loocke, Wouter
AU - Gartlgruber, Moritz
AU - Nunes, Carolina
AU - De Vloed, Fanny
AU - Depuydt, Pauline
AU - Verboom, Karen
AU - Rombaut, Dries
AU - Loontiens, Siebe
AU - De Wyn, Jolien
AU - Kholosy, Waleed M.
AU - Koopmans, Bianca
AU - Essing, Anke H.W.
AU - Herrmann, Carl
AU - Dreidax, Daniel
AU - Durinck, Kaat
AU - Deforce, Dieter
AU - van Nieuwerburgh, Filip
AU - Henssen, Anton
AU - Versteeg, Rogier
AU - Boeva, Valentina
AU - Schleiermacher, Gudrun
AU - van Nes, Johan
AU - Mestdagh, Pieter
AU - Vanhauwaert, Suzanne
AU - Schulte, Johannes H.
AU - Westermann, Frank
AU - Molenaar, Jan J.
AU - De Preter, Katleen
AU - Speleman, Frank
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.
AB - Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=85056709748&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-06699-9
DO - 10.1038/s41467-018-06699-9
M3 - Article
C2 - 30451831
AN - SCOPUS:85056709748
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4866
ER -