EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness

Autor: Bruno Ragazzon, Jean-Christophe Pointud, Houda Tabbal, Pierre Val, Igor Tauveron, Coralie Drelon, M. Batisse-Lignier, Cyril Djari, Stéphanie Rodriguez, Anne-Marie Lefrançois-Martinez, Amandine Septier, Jérôme Bertherat, Guillaume Assié, Isabelle Sahut-Barnola, Mickael Mathieu, Antoine Martinez
Přispěvatelé: Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Clermont-Ferrand, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Rok vydání: 2019
Předmět:
Cancer Research
Adenosine
Indoles
Cell Cycle Proteins
MESH: Adrenal Cortex Neoplasms
MESH: Mice
Knockout
MESH: Proportional Hazards Models
MESH: Adrenocortical Carcinoma
0302 clinical medicine
Gene expression
Adrenocortical Carcinoma
E2F1
MESH: Animals
Mice
Knockout
MESH: Chromatin Immunoprecipitation
MESH: Indoles
Regulation of gene expression
biology
EZH2
MESH: Gene Expression Regulation
Neoplastic
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
MESH: Ribonucleoside Diphosphate Reductase
3. Good health
Gene Expression Regulation
Neoplastic
Securin
MESH: E2F1 Transcription Factor
Histone
Oncology
030220 oncology & carcinogenesis
MESH: Computational Biology
Chromatin Immunoprecipitation
Ribonucleoside Diphosphate Reductase
[SDV.CAN]Life Sciences [q-bio]/Cancer
macromolecular substances
Article
Adrenal tumours
MESH: Multivariate Analysis
03 medical and health sciences
MESH: Cell Cycle Proteins
Cancer epigenetics
MESH: Cell Proliferation
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
MESH: Enhancer of Zeste Homolog 2 Protein
Animals
Humans
Enhancer of Zeste Homolog 2 Protein
Transcription factor
Cell Proliferation
Proportional Hazards Models
MESH: Humans
Cell growth
Computational Biology
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
MESH: Adenosine
Adrenal Cortex Neoplasms
MESH: Securin
[SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics
[SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis
Multivariate Analysis
biology.protein
Cancer research
Chromatin immunoprecipitation
E2F1 Transcription Factor
Zdroj: British Journal of Cancer
British Journal of Cancer, Cancer Research UK, 2019, 121 (5), pp.384-394. ⟨10.1038/s41416-019-0538-y⟩
British Journal of Cancer, 2019, 121 (5), pp.384-394. ⟨10.1038/s41416-019-0538-y⟩
ISSN: 1532-1827
0007-0920
Popis: International audience; BACKGROUND: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription. METHODS: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis. RESULTS: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC. CONCLUSIONS: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness. British Journal of Cancer https://doi.org/10.1038/s41416-019-0538-y BACKGROUND Adrenocortical carcinomas (ACC) are endocrine malignancies associated with dismal prognosis. At diagnosis, 80% of patients present metastases reducing the 5 years survival rate below 30% for most series.
Databáze: OpenAIRE
Externí odkaz: