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EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
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2017 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 6, s. 10213-10224Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2017. Vol. 8, nr 6, s. 10213-10224
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-312396DOI: 10.18632/oncotarget.14378ISI: 000394181800106PubMedID: 28052011OAI: oai:DiVA.org:uu-312396DiVA, id: diva2:1063213
Tillgänglig från: 2017-01-09 Skapad: 2017-01-09 Senast uppdaterad: 2019-04-14Bibliografiskt granskad
Ingår i avhandling
1. Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma: Implications for Biology and Therapy
Öppna denna publikation i ny flik eller fönster >>Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma: Implications for Biology and Therapy
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Multiple myeloma (MM) is a hematological malignancy of antibody producing plasmablasts/plasma cells. MM is characterized by extensive genetic and clonal heterogeneity, which have hampered the attempts to identify a common underlying mechanism for disease establishment and development of appropriate treatment regimes. This thesis is focused on understanding the role of epigenetic regulation of gene expression mediated by the polycomb repressive complexes 1 and 2 (PRC1 and 2) in MM and their impact on disease biology and therapy.

In paper I the genome-wide distribution of two histone methylation marks; H3K27me3 and H3K4me3 were studied in plasma cells isolated from newly diagnosed MM patients or age-matched normal donors. We were able to define targets of H3K27me3, H3K4me3 and bivalent (carry both marks) which are, when compared to normal individuals, unique to MM patients. The presence of H3K27me3 correlated with silencing of MM unique H3K27me3 targets in MM patients at advanced stages of the disease. Notably, the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also showed that inhibition of the PRC2 enzymatic subunit EZH2 using highly selective inhibitors (GSK343 and UNC1999) demonstrated anti-myeloma activity using relevant in vitro models of MM. These data suggest an important role for gene repression mediated by PRC2 in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

In paper II we further explored the therapeutic potential of UNC1999, a highly selective inhibitor of EZH2 in MM. We showed that EZH2 inhibition by UNC1999 downregulated important MM oncogenes; IRF-4, XBP-1, BLIMP-1and c-MYC. These oncogenes have been previously shown to be crucial for disease establishment, growth and progression. We found that EZH2 inhibition reactivated the expression of microRNAs genes previously found to be underexpressed in MM and which possess potential tumor suppressor functions. Among the reactivated microRNAs we identified miR-125a-3p and miR-320c as predicted negative regulators of the MM-associated oncogenes. Notably, we defined miR-125a-3p and miR-320c as targets of EZH2 and H3K27me3 in MM cell lines and patients samples.  These findings described for the first time PRC2/EZH2/H3K27me3 as regulators of microRNA with tumor suppressor functions in MM. This further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

In paper III we evaluated the therapeutic potential of targeting PRC1 in MM using the recently developed chemical PTC-209; an inhibitor targeting the BMI-1 subunit of PRC1. Using MM cell lines and primary cells isolated from newly diagnosed or relapsed MM patients, we found that PTC-209 has a potent anti-MM activity. We showed, for the first time in MM, that PTC-209 anti-MM effects were mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, but that other subunits of the PRC1 complex were not affected. We showed that PTC-209 reduced MM cell viability via significant induction of apoptosis. More importantly, we demonstrated that PTC-209 shows synergistic anti-MM activity with other epigenetic inhibitors targeting EZH2 (UNC1999) and BET-bromodomains (JQ1). This work highlights the potential use of BMI-1 and PRC1 as potential therapeutic targets in MM alone or in combination with other anti-MM agents including epigenetic inhibitors.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 53
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1296
Nyckelord
Multiple Myeloma, Epigenetics, Polycomb, PRC2, PRC1, EZH2, BMI-1, UNC1999, PTC-209, Epigenetic Therapy
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
Medicinsk vetenskap; Molekylär medicin
Identifikatorer
urn:nbn:se:uu:diva-312250 (URN)978-91-554-9805-4 (ISBN)
Disputation
2017-03-16, Rudbeck Hall, Rudbecklaboratoriet, 751 85 Uppsala, Sweden, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-02-21 Skapad: 2017-01-08 Senast uppdaterad: 2017-02-21
2. The Epigenome of Multiple Myeloma: From genome-wide analysis to pharmacological manipulation
Öppna denna publikation i ny flik eller fönster >>The Epigenome of Multiple Myeloma: From genome-wide analysis to pharmacological manipulation
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Nowadays epigenetic dysregulation is known to play a crucial role in virtually all cancers. In multiple myeloma (MM), an extensively heterogeneous malignancy, the key common feature among patients is the gene silencing imposed by the PRC2 complex through the addition of H3K27me3. This thesis focuses on the exploration of the MM epigenomic landscape, with an emphasis on both the interplay between H3K27me3 and other epigenetic tags, and on the effects of a series of inhibitors altering this profile.

In paper I we provide the genome-wide H3K27me3 distribution unique to MM and demonstrate that the silencing of genes in the profile correlates with an advanced and poor-outcome disease. Reduction of H3K27me3 using the EZH2 inhibitor UNC1999 reactivates genes with anti-tumor activity and induces apoptosis in vitro.

EZH2 inhibition also leads to downregulation of the MM oncogenes IRF-4, BLIMP-1, XBP-1 and c-MYC. Paper II identifies miR-125a-3p and miR-320c, predicted to target these oncogenes, as part of the PRC2 targets induced upon treatment.

In addition, H3K27me3 can be recognized and bound by the PRC1 complex. In paper III we show that inhibition of PRC1 using PTC-209 induces apoptosis and this is further enhanced when PTC-209 is combined with UNC1999. Moreover, PTC-209 has been previously shown to reduce the expression of c-MYC. Combined treatment using PTC-209 and JQ1, demonstrated to downregulate c-MYC, results in additive and synergistic effects in reducing MM cell viability.

In paper IV we present the first catalogue of genomic regulatory regions in normal plasma cells, as predicted by their combinations of histone marks. Using this, we demonstrate that in MM a subset of TSSs and enhancers become targeted by H3K27me3 and display high DNA methylation, pointing towards a possible silencing. Conversely, poised TSSs lose H3K27me3 and seemingly become de novo activated. Furthermore, we show that EZH2 physically interacts with the DNA methyltransferase DNMT1 and that combined inhibition using UNC1999 and the DNA hypomethylating agent AZA blocks the G2/M arrest triggered by AZA and induces apoptosis.

In summary, this thesis highlights the complex interconnectivity of epigenetic mechanisms in MM and provides proof-of-principle of the anti-MM effects derived from inhibiting epigenetic components in single or combinatorial regimens.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 58
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1571
Nyckelord
Multiple myeloma, epigenetics, Polycomb, EZH2, miRNA, DNA methylation, inhibitor.
Nationell ämneskategori
Medicinsk genetik Cancer och onkologi Genetik
Forskningsämne
Experimentell patologi
Identifikatorer
urn:nbn:se:uu:diva-377438 (URN)978-91-513-0650-6 (ISBN)
Disputation
2019-06-07, Rudbecksalen, Rudbecklaboratoriet - Dag Hammarskjölds väg 20, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-05-16 Skapad: 2019-04-14 Senast uppdaterad: 2019-06-18

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