Histone H3 Lysine 4 Demethylation Is a Target of Nonselective Antidepressive Medications

Lee, Min Gyu; Wynder, Christopher; Schmidt, Dawn M. Z.; McCafferty, Dewey G.; Shiekhattar, Ramin

doi:10.1016/j.chembiol.2006.05.004

Cited by 399 publications

(373 citation statements)

References 34 publications

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“…Several epigenetic cancer therapies targeting histone acetylation and DNA methylation have been established in the clinics, and the enzymes or protein complexes involved in modifying histone methylation are considered to be highly attractive drug targets. KDMs can be non-specifically targeted by amine oxidases inhibitors, which are currently indicated as antidepressants (Lee et al, 2006). Recent reports showed that PrCa cell lines respond to MAOA inhibitors, possibly via inhibition of KDM's (Flamand et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

et al. 2011

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Our understanding of key epigenetic regulators involved in specific biological processes and cancers is still incomplete, despite great progress in genome-wide studies of the epigenome. Here, we carried out a systematic, genomewide analysis of the functional significance of 615 epigenetic proteins in prostate cancer (PrCa) cells. We used the high-content cell-spot microarray technology and siRNA silencing of PrCa cell lines for functional screening of cell proliferation, survival, androgen receptor (AR) expression, histone methylation and acetylation. Our study highlights subsets of epigenetic enzymes influencing different cancer cell phenotypes. Plant homeo domain (PHD) finger proteins have a key role in cell survival and histone methylation, whereas histone deacetylases were primarily involved in regulating AR expression. In contrast, JumonjiC-domain (JmjC) containing histone lysine demethylases (KDMs) mainly had an impact on cell proliferation. Our results show that the KDMs JARID1B, PHF8, KDM3A, KDM3B and KDM4A were highly expressed in clinical PrCa samples. The PHD-finger protein 8 (PHF8), a transcriptional coactivator with both PHD-and JmjC-domains, was moderately to strongly expressed in 80% of clinical PrCa samples, whereas 76% of normal and benign samples were negative or only showed weak PHF8 expression. Strong PHF8 expression correlated significantly with high Gleason grade and was borderline significant for poor prognosis. The results of functional PHF8 knockdown implicate a role in cell migration and invasion, as shown by cell motility and 3-D invasion assays. Our study suggests that various cellular phenotypes are regulated by distinct subsets of epigenetic enzymes. Proteins interpreting and modifying histone methylation, such as JmjC-domain and particularly PHDfinger proteins like PHF8, are activated in subsets of PrCa's and promote cancer relevant phenotypes.

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Section: Discussionmentioning

confidence: 99%

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

et al. 2011

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“…In the brain, the epigenetic machinery covers basic phenomena such as differentiation, the preservation of tissue specific transcription profiles, as well as complex processes from synaptic plasticity to learning and memory. 21 Mutations and maladaptations of the epigenetic system on the level of DNA methylation, histone acetylation, and methylation are implied in neuro-developmental 22,23 and neurodegenerative 24,25 contexts, as well as neuropsychiatric diseases 26,27 and drug addiction 28,29 (for a review, see Graff et al 30 ). More specifically, the role of HDACs as regulators of transcription has been identified to be fundamental, and perturbation of acetylation homeostasis is now acknowledged to be a central event in neurologic pathologies.…”

Section: Cerebral Ischemia and Endogenous Tolerancementioning

confidence: 99%

Epigenetic Mechanisms in Cerebral Ischemia

Schweizer

Meisel

Märschenz

2013

J Cereb Blood Flow Metab

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Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration.

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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.…”

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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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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Histone H3 Lysine 4 Demethylation Is a Target of Nonselective Antidepressive Medications

Cited by 399 publications

References 34 publications

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

Epigenetic Mechanisms in Cerebral Ischemia

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

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