title: EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression.
abstract: Adrenal Cortex Carcinoma (ACC) is an aggressive tumour with poor prognosis. Common alterations in patients include constitutive WNT/β-catenin signalling and overexpression of the growth factor IGF2. However, the combination of both alterations in transgenic mice is not sufficient to trigger malignant tumour progression, suggesting that other alterations are required to allow development of carcinomas. Here, we have conducted a study of publicly available gene expression data from three cohorts of ACC patients to identify relevant alterations. Our data show that the histone methyltransferase EZH2 is overexpressed in ACC in the three cohorts. This overexpression is the result of deregulated P53/RB/E2F pathway activity and is associated with increased proliferation and poorer prognosis in patients. Inhibition of EZH2 by RNA interference or pharmacological treatment with DZNep inhibits cellular growth, wound healing and clonogenic growth and induces apoptosis of H295R cells in culture. Further growth inhibition is obtained when DZNep is combined with mitotane, the gold-standard treatment for ACC. Altogether, these observations suggest that overexpression of EZH2 is associated with aggressive progression and may constitute an interesting therapeutic target in the context of ACC.
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Drelon
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.|Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892-1103, USA.
authors.forename: Annabel
authors.initials: A
authors.lastname: Berthon
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Mathieu
authors.affiliation: Inserm U1016, CNRS UMR 8104, Université Paris Descartes, Institut Cochin, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.affiliation: Department of Biostatistics, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors.forename: Rork
authors.initials: R
authors.lastname: Kuick
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Houda
authors.initials: H
authors.lastname: Tabbal
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Septier
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.|Centre Hospitalier Universitaire, Service d'Endocrinologie, Faculté de Médecine, F- 63000 Clermont-Ferrand, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Batisse-Lignier
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sahut-Barnola
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Typhanie
authors.initials: T
authors.lastname: Dumontet
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Pointud
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lefrançois-Martinez
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Silvère
authors.initials: S
authors.lastname: Baron
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.affiliation: Inserm U1016, CNRS UMR 8104, Université Paris Descartes, Institut Cochin, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Martinez
authors.affiliation: CNRS, UMR6293, GReD, Inserm U1103, Clermont Université, F-63001 Clermont-Ferrand, France pierre.val@univ-bpclermont.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Val
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D030561:Databases, Nucleic Acid; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D034622:RNA Interference; D012307:Risk Factors; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics
chemical_list: C035170:IGF2 protein, human; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein