EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions

Mohammad Alzrigat, Alba Atienza Párraga, Prasoon Agarwal, Hadil Zureigat, Anders österborg, Hareth Nahi, Anqi Ma, Jian Jin, Kenneth Nilsson, Fredrik öberg, Antonia Kalushkova, Helena Jernberg-Wiklund

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish
Pages (from-to)10213-10224
Number of pages12
JournalOncotarget
Volume8
Issue number6
DOIs
StatePublished - 2017

Keywords

  • EZH2
  • H3K27me3
  • MicroRNA
  • Multiple myeloma
  • UNC1999

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