Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9

Greiner, Dorothea; Bonaldi, Tiziana; Eskeland, Ragnhild; Roemer, Ernst; Imhof, Axel

doi:10.1038/nchembio721

Cited by 474 publications

(398 citation statements)

References 13 publications

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“…Chaetocin is a fungal mycotoxin specifically inhibiting the variegation 3-9 homolog 1 (SUV39H1) enzyme. 18 Chaetocin displayed anticancer properties against multiple myeloma via oxidative stress induction. 19 SUV39H1 is the main HMT responsible for the accumulation of histone H3 containing a tri-methyl group at its lysine 9 position (H3K9me3) in heterochromatin.…”

Section: Introductionmentioning

confidence: 99%

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

et al. 2011

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Epigenetic deregulation is involved in acute myeloid leukemia (AML) pathogenesis and epigenetic targeting drugs are in clinical trial. Since the first results with histone-deacetylase inhibitors in AML are controversial, novel single and combined treatments need to be explored. It is tempting to combine chromatin-targeting drugs. SUV39H1, the main methyl-transferase for lysine 9 tri-methylation on histone H3, interacts with oncogenes involved in AML and acts as a transcriptional repressor for hematopoietic differentiation and immortalization. We report here that pharmacological inhibition of SUV39H1 by chaetocin induces apoptosis in leukemia cell lines in vitro and primary AML cells ex vivo, and that it interferes with leukemia growth in vivo. Chaetocin treatment upregulates reactive oxygen species (ROS) production as well as the transcription of death-receptor-related genes, in a ROS-dependent manner, leading to death receptor-dependent apoptosis. In addition to its direct inhibition by chaetocin, SUV39H1 is indirectly modulated by chaetocin-induced ROS. Accordingly, chaetocin potentiates other anti-AML drugs, in a ROS-dependent manner. The decryption of a dual mechanism of action against AML involving both direct and indirect SUV39H1 modulation represents an innovative read-out for the anticancer activity of chaetocin and for its synergy with other anti-AML drugs, suggesting new therapeutic combination strategies in AML.

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Section: Introductionmentioning

confidence: 99%

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

et al. 2011

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“…32,33 Furthermore, we have shown that a HDAC inhibitor, trichostatin A, alleviates Evi-1-mediated repression of TGF-b signalling. 16 Therefore, combined epigenetic therapy with the HMT and the HDAC inhibitors may exert synergistic activity against EVI-1-expressing leukaemic cells, and it also needs to be evaluated in the future.…”

Section: Discussionmentioning

confidence: 99%

EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization

et al. 2009

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The ecotropic viral integration site-1 (EVI-1) is a nuclear transcription factor and has an essential function in the proliferation/maintenance of haematopoietic stem cells. Aberrant expression of EVI-1 has been frequently found in myeloid leukaemia as well as in several solid tumours, and is associated with a poor patient survival. It was recently shown that EVI-1 associates with two different histone methyltransferases (HMTs), SUV39H1 and G9a. However, the functional roles of these HMTs in EVI-1-mediated leukemogenesis remain unclear. In this study, we showed that EVI-1 physically interacts with SUV39H1 and G9a, but not with Set9. Immunofluorescence analysis revealed that EVI-1 colocalizes with these HMTs in nuclei. We also found that the catalytically inactive form of SUV39H1 abrogates the transcriptional repression mediated by EVI-1, suggesting that SUV39H1 is actively involved in EVI-1-mediated transcriptional repression. Furthermore, RNAi-based knockdown of SUV39H1 or G9a in Evi-1-expressing progenitors significantly reduced their colony-forming activity. In contrast, knockdown of these HMTs did not impair bone marrow immortalization by E2A/HLF. These results indicate that EVI-1 forms higher-order complexes with HMTs, and this association has a role in the transcription repression and bone marrow immortalization. Targeting these HMTs may be of therapeutic benefit in the treatment for EVI-1-related haematological malignancies.

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“…A few small molecule compounds such as chaetocin, 254 BIX-01294, 217 BIX-01338, 217 UNC0224, 255 DZNep 256 ( Figure 15) have been identified with anti-HKMT activity by random or virtual screening approaches. The first inhibitor of HKMTs is a natural fungal substance named chaetocin.…”

Section: Inhibitors Of Hkmtsmentioning

confidence: 99%

“…The activity of chaetocin against hSU(VAR)3-9 in cells and its cytotoxic effects were observed. 254 BIX-01294 inhibits dimethylation of lysine 9 on histone H3 (H3K9me2) at low micromolar level and is an uncompetitive inhibitor against AdoMet. BIX-01294 acts as an inhibitor against G9a in vitro (IC 50 = 2.7 μM) and does not affect the activity of SUV39H1 or PRMT1.…”

Section: Inhibitors Of Hkmtsmentioning

confidence: 99%

Chemical and biochemical approaches in the study of histone methylation and demethylation

Luo

Wang

et al. 2010

Med. Res. Rev.

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Histone methylation represents one of the most critical epigenetic events in DNA function regulation in eukaryotic organisms. Classic molecular biology and genetics tools provide significant knowledge about mechanisms and physiological roles of histone methyltransferases and demethylases in various cellular processes. In addition to this stream line, development and application of chemistry and chemistry-related techniques are increasingly involved in biological study, and provide information otherwise difficulty to obtain by standard molecular biology methods. Herein, we review recent achievements and progress in developing and applying chemical and biochemical approaches in the study of histone methylation, including chromatin immunoprecipitation (ChIP), chemical ligation, mass spectrometry (MS), biochemical assays, and inhibitor development. These technological advances allow histone methylation to be studied from genome-wide level to molecular and atomic levels. With ChIP technology, information can be obtained about precise mapping of histone methylation patterns at specific promoters, genes or other genomic regions. MS is particularly useful in detecting and analyzing methylation marks in histone and nonhistone protein substrates. Chemical approaches that permit site-specific incorporation of methyl groups into histone proteins greatly facilitate the investigation of the biological impacts of methylation at individual modification sites. Discovery and design of selective organic inhibitors of histone methyltransferases and demethylases provide chemical probes to interrogate methylation-mediated cellular pathways. Overall, these chemistry-related technological advances have greatly improved our understanding of the biological functions of histone methylation in normal physiology and diseased states, and also are of great potential to translate basic epigenetics research into diagnostic and therapeutic application in the clinic.

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Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9

Cited by 474 publications

References 13 publications

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization

Chemical and biochemical approaches in the study of histone methylation and demethylation

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