title: EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes.
abstract: 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 deregulation 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 reexpression 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 with untreated cells. The antitumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together, our data suggest that EZH2 inhibition may provide a new therapy for multiple myeloma treatment and a promising addition to current treatment options. Mol Cancer Ther; 15(2); 287-98. ©2015 AACR.
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Henar
authors.initials: H
authors.lastname: Hernando
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Gelato
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Lesche
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Beckmann
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Koehr
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Otto
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Steigemann
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany. carlo.stresemann@bayer.com.
authors.forename: Carlo
authors.initials: C
authors.lastname: Stresemann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D025521:Tumor Suppressor Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2