Molecular mechanisms regulated by the histone methyltransferase EZH2 in adrenocortical carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a highly aggressive cancer. Although surgical resection remains the treatment of choice in localized ACC, clinical management of metastatic disease is ineffective. It is thus essential to identify the actors of malignant ACC progression to allow development of more effective therapeutic strategies. Deregulation of epigenetic factors is frequently involved in tumor progression. We have recently shown that the histone methyltransferase EZH2 is the most deregulated epigenetic histone modifier in ACC. EZH2 is over expressed downstream of TP53/RB1/E2F1 and is associated with tumor proliferation and poor prognosis. Pharmacological inhibition of EZH2 inhibits H295R cells growth and aggressive behaviour and induces apoptosis. This suggests that EZH2 is involved in malignant progression and could represent an interesting therapeutic target. Expression of the pro-apoptotic factor NOV/CCN3 is decreased in ACC, which is correlated with poor prognosis. Our molecular analyses show that EZH2 inhibition by siRNA or pharmacological treatment with DZNep increases expression of NOV/CCN3, suggesting that EZH2 over expression may favour malignant progression in ACC by inhibition of apoptosis stimulators. NOV has previously been identified as a negative target of the nuclear receptor SF1 in ACC cells, although the molecular mechanisms underlying this inhibition were unidentified. Interestingly, in prostate cancer, NOV expression is inhibited by the androgen receptor, through recruitment of EZH2 and deposition of the H3K27me3 mark. We are now conducting a combination of transfection and ChIP experiments to evaluate a similar cooperation between SF1 and EZH2 to repress NOV expression and block apoptosis in ACC.