Identification of Cell-Active Lysine Specific Demethylase 1-Selective Inhibitors

Ueda, Rie; Suzuki, Takayoshi; Mino, Koshiki; Tsumoto, Hiroki; Nakagawa, Hidehiko; Hasegawa, Makoto; Sasaki, Ryuzo; Mizukami, Tamio; Miyata, Naoki

doi:10.1021/ja907055q

Cited by 178 publications

(174 citation statements)

References 12 publications

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“…3e). To determine whether the demethylase activity of Lsd1 accounts for the observed migration phenotype, we additionally performed migration analysis of wild-type TSC in the presence of specific Lsd1 inhibitors 31,32 . Similar to the deletion of Lsd1, inhibitor treatment causes a significant increase in TSC migration indicating that the enzymatic activity of Lsd1 is essential ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cell migration and invasion were monitored using the xCelligence system (Roche). 1-(4-methylpiperazin-1-yl) ethan-1-one) 32 , substance 2 (trans-N-[1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]-2-phenylcyclopropan-1-amine) 31 , substance 3 (trans-N-[(2-methoxypyridin-3-yl) methyl]-2-phenylcyclopropan-1-amine) 31 or DMSO. Cell indices were automatically recorded every 15 min.…”

Section: Methodsmentioning

confidence: 99%

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Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

et al. 2014

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Propagation and differentiation of stem cell populations are tightly regulated to provide sufficient cell numbers for tissue formation while maintaining the stem cell pool. Embryonic parts of the mammalian placenta are generated from differentiating trophoblast stem cells (TSCs) invading the maternal decidua. Here we demonstrate that lysine-specific demethylase 1 (Lsd1) regulates differentiation onset of TSCs. Deletion of Lsd1 in mice results in the reduction of TSC number, diminished formation of trophectoderm tissues and early embryonic lethality. Lsd1-deficient TSCs display features of differentiation initiation, including alterations of cell morphology, and increased migration and invasion. We show that increased TSC motility is mediated by the premature expression of the transcription factor Ovol2 that is directly repressed by Lsd1 in undifferentiated cells. In summary, our data demonstrate that the epigenetic modifier Lsd1 functions as a gatekeeper for the differentiation onset of TSCs, whereby differentiation-associated cell migration is controlled by the transcription factor Ovol2.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

et al. 2014

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“…LSD1 knockout mice die early in development (15), and LSD1-null embryonic stem cells showed impaired viability (16), suggesting that LSD1 plays a crucial role in cell functions. Several studies showed that overexpression of LSD1 drives cell proliferation in various cancers (17)(18)(19)(20). We have recently found that LSD1 suppresses mitochondrial respiration and maintains energy storage in murine adipocytes under the obese condition (21).…”

Section: Introductionmentioning

confidence: 97%

Lysine Demethylase LSD1 Coordinates Glycolytic and Mitochondrial Metabolism in Hepatocellular Carcinoma Cells

et al. 2015

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The hallmark of most cancer cells is the metabolic shift from mitochondrial to glycolytic metabolism for adapting to the surrounding environment. Although epigenetic modification is intimately linked to cancer, the molecular mechanism, by which epigenetic factors regulate cancer metabolism, is poorly understood. Here, we show that lysine-specific demethylase-1 (LSD1, KDM1A) has an essential role in maintaining the metabolic shift in human hepatocellular carcinoma cells. Inhibition of LSD1 reduced glucose uptake and glycolytic activity, with a concurrent activation of mitochondrial respiration. These metabolic changes coexisted with the inactivation of the hypoxia-inducible factor HIF1a, resulting in a decreased expression of GLUT1 and glycolytic enzymes. In contrast, during LSD1 inhibition, a set of mitochondrial metabolism genes was activated with the concomitant increase of methylated histone H3 at lysine 4 in the promoter regions. Consistently, both LSD1 and GLUT1 were significantly overexpressed in carcinoma tissues. These findings demonstrate the epigenetic plasticity of cancer cell metabolism, which involves an LSD1-mediated mechanism.

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“…40,277 Recently, based on the crystal structures of FAD-PCPA adduct and the FAD-N-propargyl lysine peptide adduct complex with LSD1 279,280 , Ueda and coworkers designed a series of PCPA-lysine hybrid compounds and evaluated their inhibitory activities targeting at LSD1 and MAO-A and MAO-B. 281 Among the four synthesized compounds, the LSD1 inhibitory activities of compound 1 and 2 ( Figure 17) were over 10-fold more potent than that of PCPA (IC 50 values: PCPA = 32 μM; 1 = 2.5 μM; 2 = 1.9 μM). In particular, compound 1 and 2 specifically inhibit LSD1 in comparison to MAO-A and -B (the IC 50 values against MAO-A are 230μM and 500μM; The IC 50 against MAO-B: 290μM and >1mM).…”

Section: E Inhibitors Of Histone Lysine Demethylasesmentioning

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 Cell-Active Lysine Specific Demethylase 1-Selective Inhibitors

Cited by 178 publications

References 12 publications

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

Lysine Demethylase LSD1 Coordinates Glycolytic and Mitochondrial Metabolism in Hepatocellular Carcinoma Cells

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

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