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

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

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

Afiliación

Decaesteker B; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium. bieke.decaesteker@ugent.be.
Denecker G; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium. bieke.decaesteker@ugent.be.
Van Neste C; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Dolman EM; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Van Loocke W; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Gartlgruber M; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Nunes C; Princess Máxima Center for Pediatric Oncology, Department of Translational Research, Utrecht, 3584, The Netherlands.
De Vloed F; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Depuydt P; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Verboom K; Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
Rombaut D; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Loontiens S; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
De Wyn J; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Kholosy WM; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Koopmans B; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Essing AHW; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Herrmann C; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Dreidax D; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Durinck K; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Deforce D; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Van Nieuwerburgh F; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Henssen A; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Versteeg R; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
Boeva V; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Schleiermacher G; Princess Máxima Center for Pediatric Oncology, Department of Translational Research, Utrecht, 3584, The Netherlands.
van Nes J; Princess Máxima Center for Pediatric Oncology, Department of Translational Research, Utrecht, 3584, The Netherlands.
Mestdagh P; Princess Máxima Center for Pediatric Oncology, Department of Translational Research, Utrecht, 3584, The Netherlands.
Vanhauwaert S; Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, 69120, Germany.
Schulte JH; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
Westermann F; Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
Molenaar JJ; Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium.
De Preter K; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.
Speleman F; Cancer Research Institute Ghent (CRIG), Ghent, 9000, Belgium.

Nat Commun ; 9(1): 4866, 2018 11 19.

Article en En | MEDLINE | ID: mdl-30451831

RESUMEN

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.

Asunto(s)

Neoplasias Encefálicas/genética; Proteína Forkhead Box M1/genética; Regulación Neoplásica de la Expresión Génica; Proteínas de Interacción con los Canales Kv/genética; Proteína Proto-Oncogénica N-Myc/genética; Neuroblastoma/genética; Proteínas Represoras/genética; Proteínas de Dominio T Box/genética; Antineoplásicos/farmacología; Azepinas/farmacología; Neoplasias Encefálicas/tratamiento farmacológico; Neoplasias Encefálicas/metabolismo; Neoplasias Encefálicas/patología; Línea Celular Tumoral; Supervivencia Celular/efectos de los fármacos; Quinasas Ciclina-Dependientes/genética; Quinasas Ciclina-Dependientes/metabolismo; Variaciones en el Número de Copia de ADN; Epigénesis Genética; Proteína Forkhead Box M1/metabolismo; Células HEK293; Histonas/genética; Histonas/metabolismo; Humanos; Proteínas de Interacción con los Canales Kv/metabolismo; Proteína Proto-Oncogénica N-Myc/metabolismo; Neuroblastoma/tratamiento farmacológico; Neuroblastoma/metabolismo; Neuroblastoma/patología; Organoides/efectos de los fármacos; Organoides/metabolismo; Organoides/patología; Panobinostat/farmacología; Fenilendiaminas/farmacología; Pirimidinas/farmacología; Proteínas Represoras/metabolismo; Transducción de Señal; Proteínas de Dominio T Box/metabolismo; Triazoles/farmacología; Proteína p53 Supresora de Tumor/genética; Proteína p53 Supresora de Tumor/metabolismo; Quinasa Activadora de Quinasas Ciclina-Dependientes

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / Neoplasias Encefálicas / Regulación Neoplásica de la Expresión Génica / Proteínas de Dominio T Box / Proteínas de Interacción con los Canales Kv / Proteína Proto-Oncogénica N-Myc / Proteína Forkhead Box M1 / Neuroblastoma Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2018 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido

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