Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155135 | GEO | 2021/01/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

PALI1 Promotes Tumor Growth through Competitive Recruitment of PRC2 to G9A-target Chromatin for Dual Epigenetic Silencing [ChIP-seq]

Project description:PALI1 is a newly identified accessory protein of the Polycomb Repressive Complex 2 (PRC2) that catalyzes H3K27 methylation. However, the roles of PALI1 in cancer are yet to be defined. Here we report that PALI1 is upregulated in advanced prostate cancer (PCa) and competes with JARID2 for binding to PRC2 core subunit SUZ12. PALI1 further interacts with the H3K9 methyltransferase G9A, bridging the formation of a unique G9A-PALI1-PRC2 super-complex that occupies a subset of G9A-target genes to mediate dual H3K9/K27 methylation and gene repression. Many of these genes are developmental regulators induced upon cell differentiation, and their loss in PCa predicts poor prognosis. Accordingly, PALI1 and G9A drive PCa cell proliferation and invasion in vitro and xenograft tumor growth in vivo. Collectively, our study shows that PALI1 harnesses two central epigenetic mechanisms to suppress cellular differentiation and promote tumorigenesis, which can be targeted by dual EZH2 and G9A inhibition.

2022-12-12 | GSE212625 | GEO

PALI1 Promotes Tumor Growth through Competitive Recruitment of PRC2 to G9A-target Chromatin for Dual Epigenetic Silencing [RNA-Seq II]

2022-12-12 | GSE182144 | GEO

PALI1 Promotes Tumor Growth through Competitive Recruitment of PRC2 to G9A-target Chromatin for Dual Epigenetic Silencing

2022-12-12 | GSE175697 | GEO

PALI1 Promotes Tumor Growth through Competitive Recruitment of PRC2 to G9A-target Chromatin for Dual Epigenetic Silencing [RNA-seq]

2022-12-12 | GSE175696 | GEO

The Histone H3 Lysine 9 Methyltransferases G9a and GLP Regulate Polycomb Repressive Complex 2-Mediated Gene Silencing [ChIP-Seq]

Project description:G9a/GLP and Polycomb Repressive Complex 2 (PRC2) are two major epigenetic silencing machineries, which in particular methylate histone H3 on lysines 9 and 27 (H3K9 and H3K27), respectively. Although evidence of a crosstalk between H3K9 and H3K27 methylations has started to emerge, their actual interplay remains elusive. Here, we show that PRC2 and G9a/GLP interact physically and functionally. Moreover, combining different genome-wide approaches, we demonstrate that Ezh2 and G9a/GLP share an important number of common genomic targets, encoding developmental and neuronal regulators. Furthermore, we show that G9a enzymatic activity modulates PRC2 genomic recruitment to a subset of its target genes. Taken together, our findings demonstrate an unanticipated interplay between two main histone lysine methylation mechanisms, which cooperate to maintain silencing of a subset of developmental genes. ChIP-seq has been performed for G9a and Ezh2 in wild type TT2 mES cells or in mES cells lacking both G9a and GLP (G9a-/-GLP-/-). As a control, input DNA was saved before immunoprecipitation. Note that the two inputs (Input_TT2_0 and Input_TT2_1) have been combined and used as control for Ezh2 and G9a ChIP-seq.

2014-01-03 | E-GEOD-46536 | biostudies-arrayexpress

The Histone H3 Lysine 9 Methyltransferases G9a and GLP Regulate Polycomb Repressive Complex 2-Mediated Gene Silencing [RNA-Seq]

Project description:G9a/GLP and Polycomb Repressive Complex 2 (PRC2) are two major epigenetic silencing machineries, which in particular methylate histone H3 on lysines 9 and 27 (H3K9 and H3K27), respectively. Although evidence of a crosstalk between H3K9 and H3K27 methylations has started to emerge, their actual interplay remains elusive. Here, we show that PRC2 and G9a/GLP interact physically and functionally. Moreover, combining different genome-wide approaches, we demonstrate that Ezh2 and G9a/GLP share an important number of common genomic targets, encoding developmental and neuronal regulators. Furthermore, we show that G9a enzymatic activity modulates PRC2 genomic recruitment to a subset of its target genes. Taken together, our findings demonstrate an unanticipated interplay between two main histone lysine methylation mechanisms, which cooperate to maintain silencing of a subset of developmental genes. RNA-seq has been perform in triplicate on mES cell (TT2 : Wildtype, and KO G9a-/-)

2014-01-03 | E-GEOD-49669 | biostudies-arrayexpress

The Histone H3 Lysine 9 Methyltransferases G9a and GLP Regulate Polycomb Repressive Complex 2-Mediated Gene Silencing [Affymetrix]

Project description:G9a/GLP and Polycomb Repressive Complex 2 (PRC2) are two major epigenetic silencing machineries, which in particular methylate histone H3 on lysines 9 and 27 (H3K9 and H3K27), respectively. Although evidence of a crosstalk between H3K9 and H3K27 methylations has started to emerge, their actual interplay remains elusive. Here, we show that PRC2 and G9a/GLP interact physically and functionally. Moreover, combining different genome-wide approaches, we demonstrate that Ezh2 and G9a/GLP share an important number of common genomic targets, encoding developmental and neuronal regulators. Furthermore, we show that G9a enzymatic activity modulates PRC2 genomic recruitment to a subset of its target genes. Taken together, our findings demonstrate an unanticipated interplay between two main histone lysine methylation mechanisms, which cooperate to maintain silencing of a subset of developmental genes. Microarray has been perform in triplicate on total extract RNA from mES cell (TT2 : Wildtype and KOs G9a-/-, GLP-/-, G9a-/- and GLP-/-)

2014-01-03 | E-GEOD-46544 | biostudies-arrayexpress

Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [ChIP-seq]

Project description:Multiple myeloma (MM) is a hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs due to a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells exhibit cancer stem cell-like characteristics in MM; thus targeting these cells is a promising strategy to completely cure this malignancy. Here, we showed that SP cells expressed higher levels of enhancer of zeste (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1/2 are both potential therapeutic targets to eradicate myeloma stem cells. A novel EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including in a patient-derived xenograft model. Moreover, long-term continuous administration of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling, and over-activation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells. Our results demonstrate that dual inhibition of EZH1/2 is a promising therapeutic approach to eradicate myeloma stem cells, leading to significant advances in the treatment of MM.

2019-01-25 | GSE109674 | GEO

Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [RNA-seq]

2019-01-25 | GSE109673 | GEO

The Histone H3 Lysine 9 Methyltransferases G9a and GLP Regulate Polycomb Repressive Complex 2-Mediated Gene Silencing [RNA-Seq]

2014-01-03 | GSE49669 | GEO