1. EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness
- Author
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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, 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)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
- Subjects
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 - Abstract
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.
- Published
- 2019