LSD1 collaborates with EZH2 to regulate expression of interferon-stimulated genes

Jin, Yue; Huo, Bo; Fu, Xueqi; Tian, Haijun; Guo, Yidi; Hu, Xin

doi:10.1016/j.biopha.2017.01.055

Cited by 26 publications

(17 citation statements)

References 23 publications

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“…MYC, an aberrantly expressed transcription factor in many cancers including MM [ 46 ], is enriched in most of our transcriptomic profiles, has significantly lowered expression (Figure 4D ) upon treatment with single agent EPZ-6438/combination in both HMCLs, and is strongly predicted to be deactivated upon combination treatment in both lines. Several additional hits have also been previously proposed to directly or indirectly interact with EZH2 including NFKB [ 47 ], STAT1 [ 48 ], MYC [ 49 , 50 ], TP53 [ 15 , 47 ] and SMARCA4 [ 51 ]. IRF4, a late B-cell transcription factor, has recently been shown to facilitate EZH2i-sensitivity through BCL6-mediated downregulation in HMCLs harboring a UTX/KDM6A mutant background [ 34 ].…”

Section: Resultsmentioning

confidence: 99%

“…Canonical pathway analysis yielded many results that reflected some of the same genes enriched in upstream regulators. Some of the strongest and most consistent enrichments included the interferon signaling pathway and the antigen presentation pathway, both of which were enriched after EPZ-6438 single agent treatment and the combination and have been shown to be directly modulated by EZH2 [ 48 ]. The interferon pathway has long been considered a target for therapeutic activation in MM [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

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EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

2018

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Multiple myeloma (MM) remains a largely incurable hematologic cancer due to an inability to broadly target inevitable drug-resistant relapse. Epigenetic abnormalities are abundantly present in multiple myeloma and have increasingly demonstrated critical roles for tumor development and relapse to standard therapies. Accumulating evidence suggests that the histone methyltransferase EZH2 is aberrantly active in MM. We tested the efficacy of EZH2 specific inhibitors in a large panel of human MM cell lines (HMCLs) and found that only a subset of HMCLs demonstrate single agent sensitivity despite ubiquitous global H3K27 demethylation. Pre-treatment with EZH2 inhibitors greatly enhanced the sensitivity of HMCLs to the pan-HDAC inhibitor panobinostat in nearly all cases regardless of single agent EZH2 inhibitor sensitivity. Transcriptomic profiling revealed large-scale transcriptomic alteration by EZH2 inhibition highly enriched for cancer-related pathways. Combination treatment greatly increased the scale of gene expression change with a large portion of differentially expressed genes being unique to the combination. Transcriptomic analysis demonstrated that combination treatment further perturbed oncogenic pathways and signaling nodes consistent with an antiproliferative/pro-apoptotic state. We conclude that combined inhibition of HDAC and EZH2 inhibitors is a promising therapeutic strategy to broadly target the epigenetic landscape of aggressive MM.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

2018

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“…Understanding HOTAIR activity helps elucidate the mechanism associated with lncRNA binding to PRC2, resulting in transcriptional repression through direct silencing of specific loci. EZH2, a catalytic component of PRC2 [ 46 ], can induce H3K27me3 to repress gene transcription with specificity [ 47 , 48 ]. More importantly, EZH2 is involved in multiple pathological processes related to carcinogenesis, proliferation, apoptosis and metastasis [ 49 – 51 ].…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA SNHG15 inhibits P15 and KLF2 expression to promote pancreatic cancer proliferation through EZH2-mediated H3K27me3

et al. 2017

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Long non-coding RNA (lncRNA) is emerging as an critical regulator in multiple cancers, including pancreatic cancer (PC). Recently, lncRNA SNHG15 was found to be up-regulated in gastric cancer and hepatocellular carcinoma, exerting oncogenic effects. Nevertheless, the biological function and regulatory mechanism of SNHG15 remain unclear in pancreatic cancer (PC). In this study, we reported that SNHG15 expression was also upregulated in PC tissues, and its overexpression was remarkably associated with tumor size, tumor node metastasis (TNM) stage and lymph node metastasis in patients with PC. SNHG15 knockdown inhibited proliferative capacities and suppressed apoptotic rate of PC cells in vitro, and impaired in-vivo tumorigenicity. Additionally, RNA immunoprecipitation (RIP) assays showed that SNHG15 epigenetically repressed the P15 and Kruppel-like factor 2 (KLF2) expression via binding to enhancer of zeste homolog 2 (EZH2), and chromatin immunoprecipitation assays (CHIP) assays demonstrated that EZH2 was capable of binding to promoter regions of P15 and KLF2 to induce histone H3 lysine 27 trimethylation (H3K27me3). Furthermore, rescue experiments indicated that SNHG15 oncogenic function partially involved P15 and KLF2 repression. Consistently, an inverse correlation between the expression of SNHG15 and traget genes were found in PC tissues. Our results reported that SNHG15 could act as an oncogene in PC, revealing its potential value as a biomarker for early detection and individualized therapy.

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“…for each compound complex in the model, only the last enzyme listed has catalytic activity)PRC2:KDM. Vertebrate PRC2 recruits RBP2 (H3K4 demethylase) 111 and LSD1 (H3K4 demethylase) 135 . Recruited via H3K27me3 and H2Aub to all states that contain these modifications (half-nucleosome states 2, 3, 6, 7, 9–12, (Fig.…”

Section: Methodsmentioning

confidence: 99%

Theoretical analysis of Polycomb-Trithorax systems predicts that poised chromatin is bistable and not bivalent

Sneppen¹,

Ringrose²

2019

Nat Commun

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Polycomb (PcG) and Trithorax (TrxG) group proteins give stable epigenetic memory of silent and active gene expression states, but also allow poised states in pluripotent cells. Here we systematically address the relationship between poised, active and silent chromatin, by integrating 73 publications on PcG/TrxG biochemistry into a mathematical model comprising 144 nucleosome modification states and 8 enzymatic reactions. Our model predicts that poised chromatin is bistable and not bivalent. Bivalent chromatin, containing opposing active and silent modifications, is present as an unstable background population in all system states, and different subtypes co-occur with active and silent chromatin. In contrast, bistability, in which the system switches frequently between stable active and silent states, occurs under a wide range of conditions at the transition between monostable active and silent system states. By proposing that bistability and not bivalency is associated with poised chromatin, this work has implications for understanding the molecular nature of pluripotency.

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LSD1 collaborates with EZH2 to regulate expression of interferon-stimulated genes

Cited by 26 publications

References 23 publications

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

Long non-coding RNA SNHG15 inhibits P15 and KLF2 expression to promote pancreatic cancer proliferation through EZH2-mediated H3K27me3

Theoretical analysis of Polycomb-Trithorax systems predicts that poised chromatin is bistable and not bivalent

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