Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes

Huang, Yi; Greene, Erick; Murray-Stewart, Tracy; Goodwin, Andrew C.; Baylin, Stephen B.; Woster, Patrick M.; Casero, Robert A.

doi:10.1073/pnas.0700720104

Cited by 283 publications

(349 citation statements)

References 46 publications

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“…17 One milligram peptide of histone H3 (residues [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] carrying one or two methyl groups at lysine 4 were incubated with 2 lg of GST-LSD1 in the absence or presence of Namoline. The reaction mixture was incubated in demethylation buffer for 4 hr at 37 C and analyzed by mass spectroscopy.…”

Section: Demethylase Assaymentioning

confidence: 99%

“…[7][8][9][10][11][12][13] However, these amine oxidase inhibitors including clorgyline, pargyline, tranylcypromine, polyamines and derivatives thereof, many of them do not selectively target LSD1 and therefore, limits their use as therapeutics owing to potential side effects. In this study, we found a novel and selective LSD1 inhibitor called Namoline by combining protein structure similarity clustering and in vitro screening.…”

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confidence: 99%

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Impairment of prostate cancer cell growth by a selective and reversible lysine‐specific demethylase 1 inhibitor

Willmann

Lim

Wetzel

et al. 2012

Intl Journal of Cancer

125

108

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Post-translational modifications of histones by chromatin modifying enzymes regulate chromatin structure and gene expression. As deregulation of histone modifications contributes to cancer progression, inhibition of chromatin modifying enzymes such as histone demethylases is an attractive therapeutic strategy to impair cancer growth. Lysine-specific demethylase 1 (LSD1) removes mono-and dimethyl marks from lysine 4 or 9 of histone H3. LSD1 in association with the androgen receptor (AR) controls androgen-dependent gene expression and prostate tumor cell proliferation, thus highlighting LSD1 as a drug target. By combining protein structure similarity clustering and in vitro screening, we identified Namoline, a cpyrone, as a novel, selective and reversible LSD1 inhibitor. Namoline blocks LSD1 demethylase activity in vitro and in vivo. Inhibition of LSD1 by Namoline leads to silencing of AR-regulated gene expression and severely impairs androgen-dependent proliferation in vitro and in vivo. Thus, Namoline is a novel promising starting compound for the development of therapeutics to treat androgen-dependent prostate cancer.Prostate cancer is the second leading cause of cancer deaths in Western countries. As long as tumors are prostate confined, they can be efficiently treated by surgery and/or radiation therapy in a curative intent. In cases, however, where the tumor has already disseminated an androgen ablation therapy has to be applied. 1 Patients initially respond to androgen ablation, but tumors become androgen resistant within a period of 12-18 months, 2 after which no curative treatment exists. Thus, the urgent need to identify novel therapeutic targets for the treatment of androgen-resistant prostate cancer is evident.We recently identified lysine-specific demethylase 1 (LSD1), an amine oxidase, as a novel target for prostate cancer therapy. 3 Expression of LSD1 positively correlates with the malignancy of prostate tumors. 3,4 LSD1 functions as a histone demethylase that removes mono-and dimethyl, but not trimethyl marks from either lysine 4 or lysine 9 of histone H3 (H3K4 and H3K9, respectively). 3,5 As a component of corepressor complexes, LSD1 demethylates active methyl marks at H3K4. 5,6 In comparison, when associated with the androgen receptor (AR), the enzyme removes repressive methyl marks from H3K9, thereby enhancing AR-dependent gene expression and prostate tumor cell proliferation. 3 Thus, we hypothesized that selective LSD1 inhibitors are useful precursors for the development of novel drugs for prostate cancer therapy.Previous studies showed that inhibitors of other members of the amine oxidase family also impair the activity of LSD1. 7-13 However, these amine oxidase inhibitors including clorgyline, pargyline, tranylcypromine, polyamines and derivatives thereof, many of them do not selectively target LSD1 and therefore, limits their use as therapeutics owing to potential side effects. In this study, we found a novel and selective LSD1 inhibitor called Namoline by combining protein structure similar...

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Section: Demethylase Assaymentioning

confidence: 99%

mentioning

confidence: 99%

Impairment of prostate cancer cell growth by a selective and reversible lysine‐specific demethylase 1 inhibitor

Willmann

Lim

Wetzel

et al. 2012

Intl Journal of Cancer

125

108

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“…Finally, on deprotection with trifluoroacetic acid, 3-guanidine phenyl oxazole derivatives 9 were obtained. 26 A number of N-substituted derivatives (10)(11)(12)(13)(14) were also prepared via N-acylation, N-sulfonation or N-alkylation of 6b (Scheme 2). All synthesized compounds were fully characterized by spectroscopic methods (NMR, IR, MS and HRMS).…”

Section: Communicationmentioning

confidence: 99%

“…These molecules have been used in cultured colon cancer cells to demonstrate LSD1 inhibition and resultant activation of silenced genes. 13 Peptides containing methionine as the key structural element also showed LSD1 inhibition. However, none of these molecules are likely to be selective for LSD1 or are drugable.…”

mentioning

confidence: 99%

Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties

et al. 2013

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A series of functionalized phenyl oxazole derivatives was designed, synthesized and screened in vitro for their activities against LSD1 and for effects on viability of cervical and breast cancer cells, and in vivo for effects using zebrafish embryos. These compounds are likely to act via multiple epigenetic mechanisms specific to cancer cells including LSD1 inhibition.Histones are proteins that bind to DNA and facilitate efficient 'packing' of DNA in eukaryotic cells. 1 They are highly basic in nature due to the presence of positively charged amino acid side chains causing the DNA to fold around them into compact structures (nucleosomes). The ability of histones to regulate gene expression is controlled by post-translational modifications on the N-terminal (and likely C-terminal) "tails" of the core histones which project out of the nucleosome. Modifications including phosphorylation, acetylation, methylation, ubiquitination, sumoylation and biotinylation have been identified on the histone tails. 2 The cellular roles of histone lysine acetylation/deacetylation are the best characterized of the histone modifications -acetylation normally activates transcription whereas deacetylation deactivates this process. 3 Although there are clear links to disease, 4-8 the role of histone methylation is much less understood and appears to be context dependent.LSD1 (lysine specific demethylase 1) was the first histone demethylase identified. Its discovery significantly advanced the understanding of epigenetic regulation of gene expression, changing the paradigm that methylation is a non-reversible feature of histones. 9 Histone methylation/demethylation has since been found to be an important epigenetic modification linked to activation as well as repression of transcription. Two types of histone demethylases have been discovered. The flavin-dependent demethylase LSD1 acts on lysine 4 and lysine 9 of histone H3 (H3K4 and H3K9). LSD1 selectively catalyzes the oxidation of the methyl group of mono-and dimethylated lysines resulting in an imine intermediate and generation of hydrogen peroxide. The imine product is non-enzymatically hydrolysed to generate a carbinolamine resulting in demethylated lysine and formaldehyde release. 10 The other major class, i.e. Jumonji domain-containing histone demethylases, are Fe(II) and 2-oxoglutarate dependent oxygenases that act on mono-, di-and trimethylated Lys and methylated Arg residues depending on the particular enzymes. 11 Histone demethylase activity is associated with several pathological states. Increased LSD1 expression in prostate tumors correlates significantly with relapse during therapy. 6,7 Suppressed LSD1 expression is associated with vascular smooth muscle cell inflammatory damage in a mouse model of diabetes. 8 Demethylation of p53 (tumor suppressor) by LSD1 prevents p53 interaction with its co-activator 53BP1. 5 Activation of the telomerase reverse transcriptase (hTERT) gene is known to be dependent on LSD1 levels and recruitment to the hTERT promoter. 4 Studies on LSD1 hav...

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“…240,241 Alternatively, hydrogen peroxide can be measured by the use of luminol as a chemiluminescent substrate (Figure 13). 243,244 This detection method is the same as the widely used HRP/luminol protocol in Western blotting experiments. In the reaction, luminol is oxidized by peroxide with the catalysis of HRP and results in generation of an excited state product called 3-aminophthalate*.…”

Section: B Biochemical Assays For Methyltransferase and Demethylase mentioning

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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Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes

Cited by 283 publications

References 46 publications

Impairment of prostate cancer cell growth by a selective and reversible lysine‐specific demethylase 1 inhibitor

Impairment of prostate cancer cell growth by a selective and reversible lysine‐specific demethylase 1 inhibitor

Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties

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

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