LSD1 Histone Demethylase Assays and Inhibition

Hayward, Dawn; Cole, Philip A.

doi:10.1016/bs.mie.2016.01.020

Cited by 35 publications

(21 citation statements)

References 59 publications

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“…These data demonstrate that LSD1 colocalizes with the Notch ternary complex and PRC2 on the Arf promoter (Figure 4A). Moreover, when Notch ic -infected MEFs were treated with the LSD1 inhibitor Tranylcypromine (TCP), repression of Arf transcription by Notch was blocked (Figure 4B) (36,38). We next examined the occupancy of these factors on the Arf locus in Notch ic MEF cells treated with TCP.…”

Section: Resultsmentioning

confidence: 99%

Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

Han

Ranganathan

Tzimas

et al. 2017

Molecular Cancer Research

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It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb Repressor Complex 2 (PRC2) and Lysine Demethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape and repression of transcription. The demethylase activity of LSD1 is a pre-requisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex is identified containing LSD1, PRC2 and the Notch ternary complex. These findings demonstrate a novel function of Notch and provides further insight into the mechanisms of Notch-mediated tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

Han

Ranganathan

Tzimas

et al. 2017

Molecular Cancer Research

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“…Both GGA 14 and TCP 24 The present study clearly demonstrates that the KDM1A inhibitors GGA and TCP induce cytoplasmic translocation of nuclear KDM1A. This biological process has potential to be useful for screening promising cancer-preventive epigenetic therapeutic agents targeting KDM1A, and further work to this end is warranted.…”

Section: Discussionmentioning

confidence: 52%

“…acts as an irreversible inhibitor forming a covalent adduct with the FAD cofactor of the KDM1A enzyme. 24 In the present study, we examined the direct effect of these inhibitors on the release of KDM1A protein from the nucleus. Dose-dependent release of the protein from the nuclear fraction was observed with either GGA or TCP ( Fig.…”

Section: Tcpmentioning

confidence: 99%

Cytoplasmic translocation of nuclear lysine-specific demethylase-1 (LSD1/KDM1A) in human hepatoma cells is induced by its inhibitors

Yabuta

Shidoji

2018

Preprint

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Abbreviations: ATRA, all-trans retinoic acid; CoREST, corepressor for element 1-silencing transcription factor; DIC, differential interference contrast; FA, farnesoic acid; GGOH, geranylgeraniol; GGA, geranylgeranoic acid; LSD1/KDM1A, lysine-specific demethylase-1; pHH3, phospho-histone H3(Ser10); TCP, trans-2-phenylcyclopropylamineABSTRACT Histone-modifiable lysine-specific demethylase-1 (LSD1/KDM1A) is often upregulated in many cancers, including hepatoma, and is regarded as oncoprotein. We previously reported that the hepatoma-preventive geranylgeranoic acid (GGA) inhibits KDM1A activity at the same IC 50 as that of the clinically used drug tranylcypromine, a verified inhibitor of KDM1A. Here, we report that these inhibitors induced cytoplasmic translocation of nuclear KDM1A in a human hepatoma-derived cell line.Immunofluorescence studies revealed cytoplasmic localization of KDM1A, 3 h after addition of GGA or tranylcypromine in HuH-7 cells. Geranylgeraniol and all-trans retinoic acid were both unable to induce translocation of nuclear KDM1A, whereas farnesoic acid showed the weak activity. Furthermore, GGA did not affect subcellular localization of another histone lysine-specific demethylase, KDM5A. This suggests that the inhibitor-induced translocation of nuclear KDM1A to the cytoplasm is specific for KDM1A. These data demonstrate for the first time that KDM1A inhibitors specifically induce the cytoplasmic translocation of nuclear KDM1A.

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“…This enzyme is a member of the monoamine oxidase family, which catalyzes mono-or di-demethylation of H3K4 and H4K9 through a redox reaction. Specifically, oxidation of flavin adenine dinucleotide by means of an oxygen molecule allows conversion of H3K4me and H3K4me2 into unmethylated H3K4 [34,35]. The second group of KDM enzymes, which contain the Jumonji C (JmjC) domain, has a different mechanism of action.…”

Section: Lysine Methyltransferases and Lysine Demethylasesmentioning

confidence: 99%

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

2019

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Methylation of histone 3 at lysine 79 (H3K79) is one of the principal mechanisms involved in gene expression. The histone methyltransferase DOT1L, which mono-, di-and trimethylates H3K79 using S-adenosyl-L-methionine as a co-factor, is involved in cell development, cell cycle progression, and DNA damage repair. However, changes in normal expression levels of this enzyme are found in prostate, breast, and ovarian cancer. High levels of H3K79me are also detected in acute myeloid leukaemia patients bearing MLL rearrangements (MLL-r). MLL translocations are found in approximately 80% of paediatric patients, leading to poor prognosis. DOT1L is recruited on DNA and induces hyperexpression of HOXA9 and MEIS1. Based on these findings, selective drugs have been developed to induce apoptosis in MLL-r leukaemia cells by specifically inhibiting DOT1L. The most potent DOT1L inhibitor pinometostat has been investigated in Phase I clinical trials for treatment of paediatric and adult patients with MLL-driven leukaemia, showing promising results. ARTICLE HISTORY

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LSD1 Histone Demethylase Assays and Inhibition

Cited by 35 publications

References 59 publications

Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

Cytoplasmic translocation of nuclear lysine-specific demethylase-1 (LSD1/KDM1A) in human hepatoma cells is induced by its inhibitors

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

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