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

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

PROVIDER: PRJNA345618 | ENA |

REPOSITORIES: ENA

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

Project description: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.

| S-EPMC5354653 | biostudies-literature

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

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

2017-01-10 | GSE87714 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-01-10 | GSE87716 | GEO

Unmethylated Cyc1 downregulates hyphal specific genes and upregulates hyphal suppressors in Candida albicans

Project description:Unmethylated Cyc1 downregulates hyphal specific genes and upregulates hyphal suppressors in Candida albicans

| PRJNA1020090 | ENA

Homo sapiens

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

| PRJNA345622 | ENA

Homo sapiens

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

| PRJNA345623 | ENA

Osteocyte CIITA Aggravates Osteolytic Bone Lesions in Myeloma

Project description:Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanism underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remains unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell–secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent, or treat patients with, myeloma bone disease.

2022-04-23 | GSE200987 | GEO

Super-enhancer profiling combined with CDK7 inhibition-transcripts identifies novel oncogenes of multiple myeloma.

Project description:Super-enhancer profiling combined with CDK7 inhibition-transcripts identifies novel oncogenes of multiple myeloma.

| PRJNA608768 | ENA

C-reactive protein promotes bone destruction in human myeloma by stimulating myeloma cell production of osteolytic cytokines via the CD32A-p38MAPK-twist axis

Project description:Bone destruction is a hallmark of human myeloma and affects more than 80% of patients. Although it is well established that myeloma cells mediate bone destruction by activating osteoclasts, the mechanism how myeloma cells are regulated to do so is unknown. Here we show that C-reactive protein (CRP), a protein secreted in elevated amounts by hepatocytes in response to myeloma-derived cytokines, may be responsible for activating myeloma cells to promote osteoclastogenesis and inducing bone destruction in vivo. CRP binds to surface CD32A/FcRIIA, activates p38MAPK-twist pathways, and upregulates the secretion of osteolytic cytokines by myeloma cells. Clinical studies examining the relationship between the levels of serum CRP and the numbers of osteolytic bone lesions in newly diagnosed patients support this conclusion.

2017-09-12 | GSE103697 | GEO

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