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

ABSTRACT: Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite current progress in improving patient outcome, MM remains largely incurable. Disease clonal and interpatient heterogeneity has hampered identification of a common underlying mechanism for disease establishment and have slowed the development of novel targeted therapies. Epigenetic aberrations are now emerging as increasingly important in tumorigenesis, thus selective targeting of crucial epigenetic enzymes may provide new therapeutic potential in cancer including MM. Recently, we and others suggested the histone methyltransferase enhancer of zeste homolog 2 (EZH2), to be a potential therapeutic target in MM. Now we show that pharmacological inhibition of EZH2 suppresses the MM cell growth through downregulation of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1and c-MYC. We also show that downregulation of these genes is mediated via reactivated expression of microRNAs with tumor suppressor functions; primarily miR125a-3p and miR320c. Using chromatin immunoprecipitation (ChIP) we demonstrate that miR125a-3p and miR320c are targets of EZH2 and H3K27me3 in MM cell lines and primary MM cells. Our results further highlight the importance of polycomb-mediated silencing in MM to include microRNAs with tumor suppressor activity. This novel role further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE87714 | GEO | 2017/01/10

SECONDARY ACCESSION(S): PRJNA345623

REPOSITORIES: GEO

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

Project description:Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite current progress in improving patient outcome, MM remains largely incurable. Disease clonal and interpatient heterogeneity has hampered identification of a common underlying mechanism for disease establishment and have slowed the development of novel targeted therapies. Epigenetic aberrations are now emerging as increasingly important in tumorigenesis, thus selective targeting of crucial epigenetic enzymes may provide new therapeutic potential in cancer including MM. Recently, we and others suggested the histone methyltransferase enhancer of zeste homolog 2 (EZH2), to be a potential therapeutic target in MM. Now we show that pharmacological inhibition of EZH2 suppresses the MM cell growth through downregulation of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1and c-MYC. We also show that downregulation of these genes is mediated via reactivated expression of microRNAs with tumor suppressor functions; primarily miR125a-3p and miR320c. Using chromatin immunoprecipitation (ChIP) we demonstrate that miR125a-3p and miR320c are targets of EZH2 and H3K27me3 in MM cell lines and primary MM cells. Our results further highlight the importance of polycomb-mediated silencing in MM to include microRNAs with tumor suppressor activity. This novel role further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

2017-01-10 | GSE87715 | GEO

Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [CUT&RUN]

Project description:Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2’s both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.

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Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [RNA-seq]

2023-01-25 | GSE214668 | GEO

Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology [ChIP-seq]

Project description:Multiple myeloma (MM) is a malignant B cell dyscrasia characterized by the accumulation of clonal plasma cells (PC) within the bone marrow. Epigenetic factors are involved in MM initiation, progression, and occurrence of chemoresistance. Among them EZH2, the Polycomb Repressive Complex 2 (PRC2) catalytic subunit and NSD2 (MMSET), the target oncogene of t(4;14) primary translocation, are both associated with poor prognosis values and contribute to MM disease. In this study, we identified a physical interaction between EZH2 and MMSET in MM. We used MMSET-depleted MM cells and MAK-683, an allosteric inhibitor of EZH2, to disrupt this interaction and understand its implication in MM biology and resistance to anti-MM drugs. Through its interaction with EZH2, MMSET regulates PRC2 nuclear localization in MM cells, promotes a particularly poor prognosis in MM patients, and modulates the expression of tumor-suppressor genes involved in p53 pathway. We also demonstrated that MAK-683 can interfere with this interaction and synergizes with conventional drugs used in MM treatment: Melphalan, an alkylating agent triggering DNA Damage Response (DDR); and Panobinostat, a Histone De-Acetylase (HDAC) inhibitor directedly regulating p53 acetylation and stability.

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Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology [RNA-seq]

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Dual inhibition of EZH2 and G9a suppresses multiple myeloma cell proliferation by regulating interferon signal and IRF4-MYC axis

Project description:Epigenetic mechanisms including histone modifications play key roles in the pathogenesis of multiple myeloma (MM). We have previously shown that a histone H3 lysine 27 (H3K27) methyltransferase EZH2 and a H3K9 methyltransferase G9a are potential therapeutic targets in MM. Recent studies suggested that EZH2 and G9a cooperate to regulate gene expression. We thus aimed to evaluate the anti-tumor effect by dual targeting of EZH2 and G9a in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed myeloma cell proliferation through inducing cell cycle arrest and apoptosis in vitro. Dual inhibition of EZH2 and G9a also repressed xenograft formation by myeloma cells in vivo. Higher expression levels of EZH2 and EHMT2, which encodes G9a, are significantly associated with poorer prognosis in MM patients, respectively. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in myeloma cells. Notably, we found increased expression and reduced H3K27/H3K9 methylation levels of endogenous retrovirus (ERV) genes in myeloma cells with the dual inhibition, suggesting that activation of the ERV genes may cause the IFN response. These results suggest that dual targeting of EZH2 and G9a may be a novel therapeutic strategy in MM.

2021-01-27 | GSE155135 | GEO

Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease

Project description:Multiple myeloma (MM) is a blood disease characterized by the malignant accumulation of monoclonal plasma cells in the bone marrow. Among the pathological consequences of the MM, defects in osteogenesis characterized by osteolytic lesions, osteopenia, and pathologic fractures are frequently described. Che-1/AATF (Che-1) is a co-transcriptional factor involved in MM transformation and proliferation. Here, we show that Che-1 expression in MM contributes to maintaining low level of WWTR1 (TAZ), a transcriptional coactivator downstream of the Hippo-signaling pathway. We report that the miR-590-3p, deriving from the mRNA splicing of the EIF4H host gene, can target TAZ, contributing to downregulating its expression in MM. Furthermore, we demonstrate by in vivo and in vitro experiments that Che-1 transcriptionally induces EIF4H gene. We provide data to support that miR-590-3p is secreted by MM cells in vitro and in vivo and that can inhibit TAZ levels and the physiological transcriptional expression of osteogenic-related genes, in mesenchymal stem cells. Our findings unveil an unexplored novel Che-1/miR-590-3p/TAZ axis in MM tumorigenesis by providing a rationale to explore the therapeutic potential of metastatic bone lesions.

2024-04-10 | GSE234642 | GEO

Epigenetic silencing of the tumor suppressor RASSF4 favors multiple myeloma progression

Project description:RAS is frequently mutated in multiple myeloma (MM) leading to aberrant signaling. Next to their classical oncogenic effects, RAS proteins also mediate anti-tumor effects through the Ras-Association Domain Family (RASSF) proteins. Currently, no data about the role of RASSF proteins in MM disease is available. Here we report that RASSF4 is downregulated during MM progression, correlating with a bad prognosis. Epigenetic modulating agents significantly increased RASSF4 expression, indicating that the RASSF4 downregulation is due to epigenetic silencing. Forced RASSF4 expression induced a G2-phase arrest and caspase-3 mediated apoptosis in human MM cell lines, strongly reduced viability of primary CD138+ MM cells and significantly reduced in vivo tumor growth. Moreover, we demonstrated RASSF4-MST1 binding and the involvement of the downstream signaling pathways JNK/Jun, p38 and p53. RASSF4 overexpression sensitized MM cells to the proteasome inhibitor bortezomib, the specific MEK1/2 inhibitor trametinib and the ROS inducer Prima-1Met. Consequently, combining trametinib with histone deacetylase inhibitors (HDACi) revealed very strong synergistic anti-MM activity. In conclusion, our study identified RASSF4 as a new potent tumor suppressor in MM that is epigenetically silenced during MM progression and provides the basis for novel therapeutic strategies enhancing RASSF4 expression (using HDACi) in combination with MEK/ERK inhibitors and bortezomib.

2017-07-31 | GSE85020 | GEO

A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma

Project description:Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer. While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i. By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling. Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells. This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis. Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment.

2021-02-04 | GSE152006 | GEO

Epigenetic regulation of NK cell-mediated immune response in multiple myeloma [RNA-Seq]

Project description:Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we performed two in vitro genome-wide CRISPR screens to systematically discover the regulators of sensitivity to Dara-mediated antibody-dependent cellular cytotoxicity (ADCC) and identified KDM6A. The loss of KDM6A led to a marked downregulation in CD38 expression by increasing H3K27me3 on the CD38 promoter, resulting in resistance to Dara-mediated ADCC. Yet, adding back CD38 did not completely rescue this phenotype. In fact, KDM6A loss also downregulated CD48, which promoted Dara resistance by inhibiting natural killer cell activity. Lowering the H3K27me3 with an EZH2 inhibitor restored sensitivity to Dara through CD38 and CD48 upregulation. These findings suggest KDM6A loss as a mechanism of Dara resistance and explore the strategy of using an EZH2 inhibitor, one of which is already FDA-approved, to improve the response to Dara in MM.

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