Open AccessEZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression
Author(s) -
Coralie Drelon,
Annabel Berthon,
M Mathieu,
Bruno Ragazzon,
Rork Kuick,
Houda Tabbal,
Amandine Septier,
Stéphanie Rodriguez,
Marie Batisse-Lignier,
Isabelle SahutBarnola,
Typhanie Dumontet,
Jean Christophe Pointud,
Anne Marie Lefrançois-Martinez,
Silvère Baron,
Thomas J. Giordano,
Jérôme Bertherat,
Antoine Martinez,
Pierre Val
Publication year - 2016
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddw136
Subject(s) - biology , adrenocortical carcinoma , cancer research , ezh2 , wnt signaling pathway , tumor progression , context (archaeology) , clonogenic assay , cell growth , cancer , apoptosis , endocrinology , signal transduction , epigenetics , gene , microbiology and biotechnology , genetics , paleontology
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.