EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions
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Mohammad Alzrigat1, Alba Atienza Párraga1,*, Prasoon Agarwal2,*, Hadil Zureigat3, Anders Österborg4, Hareth Nahi5, Anqi Ma6, Jian Jin6, Kenneth Nilsson1, Fredrik Öberg1, Antonia Kalushkova1, Helena Jernberg-Wiklund1
1Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
2Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska University Hospital, Huddinge, Stockholm, Sweden
3Department of Medicine, Faculty of Medicine, University of Jordan, Amman, Jordan
4Department of Oncology-Pathology, Karolinska University Hospital, Solna, Stockholm, Sweden
5Department of Medicine, Unit of Hematology, Karolinska University Hospital, Huddinge, Stockholm, Sweden
6Department of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
*These authors have contributed equally to this work
Helena Jernberg-Wiklund, email: [email protected]
Mohammad Alzrigat, email: [email protected]
Keywords: multiple myeloma, EZH2, H3K27me3, microRNA, UNC1999
Received: October 09, 2016 Accepted: December 15, 2016 Published: December 30, 2016
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.
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