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.

UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition

“…By contrast, activated B-cell lymphoma cells are not sensitive to EZH2i, and display modest transcriptional changes upon treatment (McCabe et al, 2012b, Beguelin et al, 2013). EZH2i have been recently described to decrease the expression of oncogenes and promote the expression of miRNAs with tumor suppressor functions in MM cells (Alzrigat et al, 2017). In our study, EZH2i activated a large number of genes in both UTX -mutant and wild-type MM cells, but a substantial fraction of these genes were different, with enrichment of genes involved in cell death and regulation of proliferation found exclusively in UTX -mutant cells.…”

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

“…As well, because t(4;14) MM is accompanied with a global reduction of the mark added by EZH2, H3K27me (49, 50), EZH2 inhibitors (EZH2i) have been effective at targeting MM cells with elevated levels of NSD2 (51, 61–64). Similarly, KDM6A loss in MM led to repression of a specific gene set that can be re-expressed by EZH2 inhibition, leading to cell death (65).…”

“…Similarly, KDM6A loss in MM led to repression of a specific gene set that can be re-expressed by EZH2 inhibition, leading to cell death (65). EZH2 inhibitor sensitivity in MM has been attributed to downregulation of MM oncogenes such as c-MYC, XBP-1, IRF-4, PRDM1 (64), and upregulation of epithelial tumor suppressor genes like CDH1 (63). …”

Role of epigenetics-microRNA axis in drug resistance of multiple myeloma

“…EZH2 has also been shown to interact with transcription factors which are targets of tumor suppressor miRNAs, such as MYC in lymphomas [61] and in MM [29]. Alzrigat et al demonstrated that pharmacologic inhibition of EZH2 in MM cell lines and primary cells suppressed transcription factors with oncogenic activity in MM including IRF-4, XBP-1, PRDM1/BLIMP-1, and c-MYC.…”