title: EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
abstract: Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alzrigat
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Alba Atienza
authors.initials: AA
authors.lastname: Párraga
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: Prasoon
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Department of Medicine, Faculty of Medicine, University of Jordan, Amman, Jordan.
authors.forename: Hadil
authors.initials: H
authors.lastname: Zureigat
authors.affiliation: Department of Oncology-Pathology, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Österborg
authors.affiliation: Department of Medicine, Unit of Hematology, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: Hareth
authors.initials: H
authors.lastname: Nahi
authors.affiliation: Department of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Anqi
authors.initials: A
authors.lastname: Ma
authors.affiliation: Department of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Nilsson
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Öberg
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Antonia
authors.initials: A
authors.lastname: Kalushkova
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009857:Oncogenes; D000074462:Positive Regulatory Domain I-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4; D001549:Benzamides; D007191:Indazoles; D010879:Piperazines
chemical_list: D000970:Antineoplastic Agents; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors; D050835:Interferon Regulatory Factors; D035683:MicroRNAs; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016271:Proto-Oncogene Proteins c-myc; D011728:Pyridones; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4; C531888:MIRN125 microRNA, human; C572916:MIRN320 microRNA, human; C489427:MYC protein, human; C000619732:UNC1999; D001549:Benzamides; D007191:Indazoles; D010879:Piperazines; C000605543:XBP1 protein, human; C087042:PRDM1 protein, human; C498409:EZH2 protein, human
keywords: EZH2; H3K27me3; UNC1999; microRNA; multiple myeloma