TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

Bieke Decaesteker; Geertrui Denecker; Christophe Van Neste; Emmy M Dolman; Wouter Van Loocke; Moritz Gartlgruber; Carolina Nunes; Fanny De Vloed; Pauline Depuydt; Karen Verboom; Dries Rombaut; Siebe Loontiens; Jolien De Wyn; Waleed M Kholosy; Bianca Koopmans; Anke H W Essing; Carl Herrmann; Daniel Dreidax; Kaat Durinck; Dieter Deforce; Filip Van Nieuwerburgh; Anton Henssen; Rogier Versteeg; Valentina Boeva; Gudrun Schleiermacher; Johan van Nes; Pieter Mestdagh; Suzanne Vanhauwaert; Johannes H Schulte; Frank Westermann; Jan J Molenaar; Katleen De Preter; Frank Speleman

doi:10.1038/s41467-018-06699-9

TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

Bieke Decaesteker, Geertrui Denecker, Christophe Van Neste, Emmy M Dolman, Wouter Van Loocke, Moritz Gartlgruber, Carolina Nunes, Fanny De Vloed, Pauline Depuydt, Karen Verboom, Dries Rombaut, Siebe Loontiens, Jolien De Wyn, Waleed M Kholosy, Bianca Koopmans, Anke H W Essing, Carl Herrmann, Daniel Dreidax, Kaat Durinck, Dieter DeforceFilip Van Nieuwerburgh, Anton Henssen, Rogier Versteeg, Valentina Boeva, Gudrun Schleiermacher, Johan van Nes, Pieter Mestdagh, Suzanne Vanhauwaert, Johannes H Schulte, Frank Westermann, Jan J Molenaar, Katleen De Preter, Frank Speleman

Science

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	4866
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06699-9
Publication status	Published - 19 Nov 2018

Keywords

Antineoplastic Agents/pharmacology
Azepines/pharmacology
Brain Neoplasms/drug therapy
Cell Line, Tumor
Cell Survival/drug effects
Cyclin-Dependent Kinases/genetics
DNA Copy Number Variations
Epigenesis, Genetic
Forkhead Box Protein M1/genetics
Gene Expression Regulation, Neoplastic
HEK293 Cells
Histones/genetics
Humans
Kv Channel-Interacting Proteins/genetics
N-Myc Proto-Oncogene Protein/genetics
Neuroblastoma/drug therapy
Organoids/drug effects
Panobinostat/pharmacology
Phenylenediamines/pharmacology
Pyrimidines/pharmacology
Repressor Proteins/genetics
Signal Transduction
T-Box Domain Proteins/genetics
Triazoles/pharmacology
Tumor Suppressor Protein p53/genetics

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Decaesteker, B., Denecker, G., Van Neste, C., Dolman, E. M., Van Loocke, W., Gartlgruber, M., Nunes, C., De Vloed, F., Depuydt, P., Verboom, K., Rombaut, D., Loontiens, S., De Wyn, J., Kholosy, W. M., Koopmans, B., Essing, A. H. W., Herrmann, C., Dreidax, D., Durinck, K., ... Speleman, F. (2018). TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets. Nature Communications, 9(1), 4866. https://doi.org/10.1038/s41467-018-06699-9

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title = "TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets",

abstract = "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.",

keywords = "Antineoplastic Agents/pharmacology, Azepines/pharmacology, Brain Neoplasms/drug therapy, Cell Line, Tumor, Cell Survival/drug effects, Cyclin-Dependent Kinases/genetics, DNA Copy Number Variations, Epigenesis, Genetic, Forkhead Box Protein M1/genetics, Gene Expression Regulation, Neoplastic, HEK293 Cells, Histones/genetics, Humans, Kv Channel-Interacting Proteins/genetics, N-Myc Proto-Oncogene Protein/genetics, Neuroblastoma/drug therapy, Organoids/drug effects, Panobinostat/pharmacology, Phenylenediamines/pharmacology, Pyrimidines/pharmacology, Repressor Proteins/genetics, Signal Transduction, T-Box Domain Proteins/genetics, Triazoles/pharmacology, Tumor Suppressor Protein p53/genetics",

author = "Bieke Decaesteker and Geertrui Denecker and {Van Neste}, Christophe and Dolman, {Emmy M} and {Van Loocke}, Wouter and Moritz Gartlgruber and Carolina Nunes and {De Vloed}, Fanny and Pauline Depuydt and Karen Verboom and Dries Rombaut and Siebe Loontiens and {De Wyn}, Jolien and Kholosy, {Waleed M} and Bianca Koopmans and Essing, {Anke H W} and Carl Herrmann and Daniel Dreidax and Kaat Durinck and Dieter Deforce and {Van Nieuwerburgh}, Filip and Anton Henssen and Rogier Versteeg and Valentina Boeva and Gudrun Schleiermacher and {van Nes}, Johan and Pieter Mestdagh and Suzanne Vanhauwaert and Schulte, {Johannes H} and Frank Westermann and Molenaar, {Jan J} and {De Preter}, Katleen and Frank Speleman",

year = "2018",

month = nov,

day = "19",

doi = "10.1038/s41467-018-06699-9",

language = "English",

volume = "9",

pages = "4866",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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Decaesteker, B, Denecker, G, Van Neste, C, Dolman, EM, Van Loocke, W, Gartlgruber, M, Nunes, C, De Vloed, F, Depuydt, P, Verboom, K, Rombaut, D, Loontiens, S, De Wyn, J, Kholosy, WM, Koopmans, B, Essing, AHW, Herrmann, C, Dreidax, D, Durinck, K, Deforce, D, Van Nieuwerburgh, F, Henssen, A, Versteeg, R, Boeva, V, Schleiermacher, G, van Nes, J, Mestdagh, P, Vanhauwaert, S, Schulte, JH, Westermann, F, Molenaar, JJ, De Preter, K & Speleman, F 2018, 'TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets', Nature Communications, vol. 9, no. 1, pp. 4866. https://doi.org/10.1038/s41467-018-06699-9

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

PY - 2018/11/19

Y1 - 2018/11/19

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.

KW - Antineoplastic Agents/pharmacology

KW - Azepines/pharmacology

KW - Brain Neoplasms/drug therapy

KW - Cell Line, Tumor

KW - Cell Survival/drug effects

KW - Cyclin-Dependent Kinases/genetics

KW - DNA Copy Number Variations

KW - Epigenesis, Genetic

KW - Forkhead Box Protein M1/genetics

KW - Gene Expression Regulation, Neoplastic

KW - HEK293 Cells

KW - Histones/genetics

KW - Humans

KW - Kv Channel-Interacting Proteins/genetics

KW - N-Myc Proto-Oncogene Protein/genetics

KW - Neuroblastoma/drug therapy

KW - Organoids/drug effects

KW - Panobinostat/pharmacology

KW - Phenylenediamines/pharmacology

KW - Pyrimidines/pharmacology

KW - Repressor Proteins/genetics

KW - Signal Transduction

KW - T-Box Domain Proteins/genetics

KW - Triazoles/pharmacology

KW - Tumor Suppressor Protein p53/genetics

U2 - 10.1038/s41467-018-06699-9

DO - 10.1038/s41467-018-06699-9

M3 - Article

C2 - 30451831

SN - 2041-1723

VL - 9

SP - 4866

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

Abstract

Keywords

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