EZH2 inhibition blocks multiple myeloma cell growth through upregulation of epithelial tumor suppressor genes
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes suggérant l'intérêt d'une stratégie basée sur l'inhibition de EZH2 pour le traitement des patients atteints d'un myélome multiple
Multiple myeloma is a plasma cell malignancy characterized by marked heterogeneous genomic instability including frequent genetic alterations in epigenetic enzymes. In particular the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in multiple myeloma. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a master transcriptional regulator of differentiation. EZH2 catalyzes methylation of lysine 27 on histone H3 and its de-regulation in cancer has been reported to contribute to silencing of tumor suppressor genes, resulting in a more undifferentiated state, and thereby contributing to the multiple myeloma phenotype. In this study we propose the use of EZH2 inhibitors as a new therapeutic approach for the treatment of multiple myeloma. We demonstrate that EZH2 inhibition causes a global reduction of H3K27me3 in multiple myeloma cells, promoting re-expression of EZH2 repressed tumor suppressor genes in a subset of cell lines. As a result of this transcriptional activation, multiple myeloma cells treated with EZH2 inhibitors become more adherent and less proliferative compared to untreated cells. The anti-tumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together our data suggests that EZH2 inhibition may provide a new therapy for multiple myeloma treatment, and a promising addition to current treatment options.
http://mct.aacrjournals.org/content/early/2015/11/20/1535-7163.MCT-15-0486.abstract