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Kdm1a

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https://www.readbyqxmd.com/read/28507606/transcription-and-chromatin-determinants-of-de-novo-dna-methylation-timing-in-oocytes
#1
Lenka Gahurova, Shin-Ichi Tomizawa, Sébastien A Smallwood, Kathleen R Stewart-Morgan, Heba Saadeh, Jeesun Kim, Simon R Andrews, Taiping Chen, Gavin Kelsey
BACKGROUND: Gametogenesis in mammals entails profound re-patterning of the epigenome. In the female germline, DNA methylation is acquired late in oogenesis from an essentially unmethylated baseline and is established largely as a consequence of transcription events. Molecular and functional studies have shown that imprinted genes become methylated at different times during oocyte growth; however, little is known about the kinetics of methylation gain genome wide and the reasons for asynchrony in methylation at imprinted loci...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28498828/kdm1a-lsd1-regulates-the-differentiation-and-maintenance-of-spermatogonia-in-mice
#2
Dexter A Myrick, Michael A Christopher, Alyssa M Scott, Ashley K Simon, Paul G Donlin-Asp, William G Kelly, David J Katz
The proper regulation of spermatogenesis is crucial to ensure the continued production of sperm and fertility. Here, we investigated the function of the H3K4me2 demethylase KDM1A/LSD1 during spermatogenesis in developing and adult mice. Conditional deletion of Kdm1a in the testis just prior to birth leads to fewer spermatogonia and germ cell loss before 3 weeks of age. These results demonstrate that KDM1A is required for spermatogonial differentiation, as well as germ cell survival, in the developing testis...
2017: PloS One
https://www.readbyqxmd.com/read/28469799/histone-h3k14-hypoacetylation-and-h3k27-hypermethylation-along-with-hdac1-up-regulation-and-kdm6b-down-regulation-are-associated-with-active-pulmonary-tuberculosis-disease
#3
Yung-Che Chen, Tung-Ying Chao, Sum-Yee Leung, Chung-Jen Chen, Chao-Chien Wu, Wen-Feng Fang, Yi-Hsi Wang, Huang-Chih Chang, Ting-Ya Wang, Yong-Yong Lin, Yi-Xin Zheng, Meng-Chih Lin, Chang-Chun Hsiao
The aim of this study is to determine the roles of global histone acetylation (Ac)/methylation (me), their modifying enzymes, and gene-specific histone enrichment in active pulmonary tuberculosis (TB) disease. Global histone H3K27me3, H3K27me2, H3K9me3, H3K9Ac, and H3K14Ac expressions, and their modifying enzyme expressions, including KDM1A, KDM6B, EZH2, HDAC1, and HDAC2, were assessed in blood leukocytes from 81 patients with active pulmonary TB disease and 44 matched healthy subjects (HS). TLR2, TNF-α, IFN-γ, and IL12B-specific histone enrichment of peripheral blood mononuclear cells was measured by chromatin immunoprecipitation method...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28452984/frequent-somatic-mutations-in-epigenetic-regulators-in-newly-diagnosed-chronic-myeloid-leukemia
#4
E Togasaki, J Takeda, K Yoshida, Y Shiozawa, M Takeuchi, M Oshima, A Saraya, A Iwama, K Yokote, E Sakaida, C Hirase, A Takeshita, K Imai, H Okumura, Y Morishita, N Usui, N Takahashi, S Fujisawa, Y Shiraishi, K Chiba, H Tanaka, H Kiyoi, K Ohnishi, S Ohtake, N Asou, Y Kobayashi, Y Miyazaki, S Miyano, S Ogawa, I Matsumura, C Nakaseko, T Naoe
Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17)...
April 28, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28398479/clinical-significance-of-mirna-host-gene-promoter-methylation-in-prostate-cancer
#5
Kristina Daniunaite, Monika Dubikaityte, Povilas Gibas, Arnas Bakavicius, Juozas Rimantas Lazutka, Albertas Ulys, Feliksas Jankevicius, Sonata Jarmalaite
Only a part of prostate cancer (PCa) patients has aggressive malignancy requiring adjuvant treatment after radical prostatectomy (RP). Biomarkers capable to predict biochemical PCa recurrence (BCR) after RP would significantly improve preoperative risk stratification and treatment decisions. MicroRNA (miRNA) deregulation has recently emerged as an important phenomenon in tumor development and progression, however, the mechanisms remain largely unstudied. In the present study, based on microarray profiling of DNA methylation in 9 pairs of PCa and noncancerous prostate tissues (NPT), host genes of miR-155-5p, miR-152-3p, miR-137, miR-31-5p, and miR-642a, -b were analyzed for promoter methylation in 129 PCa, 35 NPT, and 17 benign prostatic hyperplasia samples (BPH) and compared to the expression of mature miRNAs and their selected targets (DNMT1, KDM1A, and KDM5B)...
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28390942/fluorinated-tranylcypromine-analogues-as-inhibitors-of-lysine-specific-demethylase-1-lsd1-kdm1a
#6
Maria Teresa Borrello, Benjamin Schinor, Katharina Bartels, Hanae Benelkebir, Sara Pereira, Wafa T Al-Jamal, Leon Douglas, Patrick J Duriez, Graham Packham, Günter Haufe, A Ganesan
We report a series of tranylcypromine analogues containing a fluorine in the cyclopropyl ring. A number of compounds with additional m- or p-substitution of the aryl ring were micromolar inhibitors of the LSD1 enzyme. In cellular assays, the compounds inhibited the proliferation of acute myeloid leukemia cell lines. Increased levels of the biomarkers H3K4me2 and CD86 were consistent with LSD1 target engagement.
March 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28377178/targeting-kdm1a-attenuates-wnt-%C3%AE-catenin-signaling-pathway-to-eliminate-sorafenib-resistant-stem-like-cells-in-hepatocellular-carcinoma
#7
Mengxi Huang, Cheng Chen, Jian Geng, Dong Han, Tao Wang, Tao Xie, Liya Wang, Ye Wang, Chunhua Wang, Zengjie Lei, Xiaoyuan Chu
Use of the tyrosine kinase inhibitor sorafenib in patients with advanced hepatocellular carcinoma (HCC) is often hindered by the development of resistance, which has been recently shown to be associated with the emergence of a cancer stem cell (CSC) subpopulation. However, it remains largely unknown whether epigenetic mechanisms, especially histone posttranslational modifications, are causally linked to the maintenance of stem-like properties in sorafenib-resistant HCC. In this study, we report that the activity of lysine-specific histone demethylase 1A (KDM1A or LSD1) is required for the emergence of cancer stem cells following prolonged sorafenib treatment...
July 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28336409/development-and-crystallographic-evaluation-of-histone-h3-peptide-with-n-terminal-serine-substitution-as-a-potent-inhibitor-of-lysine-specific-demethylase-1
#8
Yuichi Amano, Masaki Kikuchi, Shin Sato, Shigeyuki Yokoyama, Takashi Umehara, Naoki Umezawa, Tsunehiko Higuchi
Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro...
March 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28322226/highly-effective-combination-of-lsd1-kdm1a-antagonist-and-pan-histone-deacetylase-inhibitor-against-human-aml-cells
#9
W Fiskus, S Sharma, B Shah, B P Portier, S G T Devaraj, K Liu, S P Iyer, D Bearss, K N Bhalla
No abstract text is available yet for this article.
March 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28228264/lsd1-controls-timely-myod-expression-via-myod-core-enhancer-transcription
#10
Isabella Scionti, Shinichiro Hayashi, Sandrine Mouradian, Emmanuelle Girard, Joana Esteves de Lima, Véronique Morel, Thomas Simonet, Maud Wurmser, Pascal Maire, Katia Ancelin, Eric Metzger, Roland Schüle, Evelyne Goillot, Frederic Relaix, Laurent Schaeffer
MyoD is a master regulator of myogenesis. Chromatin modifications required to trigger MyoD expression are still poorly described. Here, we demonstrate that the histone demethylase LSD1/KDM1a is recruited on the MyoD core enhancer upon muscle differentiation. Depletion of Lsd1 in myoblasts precludes the removal of H3K9 methylation and the recruitment of RNA polymerase II on the core enhancer, thereby preventing transcription of the non-coding enhancer RNA required for MyoD expression (CEeRNA). Consistently, Lsd1 conditional inactivation in muscle progenitor cells during embryogenesis prevented transcription of the CEeRNA and delayed MyoD expression...
February 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28223039/oncogene-lsd1-is-epigenetically-suppressed-by-mir-137-overexpression-in-human-non-small-cell-lung-cancer
#11
Xin Zhang, Xiujuan Zhang, Bo Yu, Rongpeng Hu, Lanxiang Hao
PURPOSE: We examined the epigenetic regulation of microRNA-137 (miR-137) on lysine-specific demethylase 1 (KDM1A, or LSD1) induced oncogenic effects in NSCLC. METHODS: NSCLC cell lines, A549 and H460 cells were transfected with a mammalian LSD1 overexpression plasmid. It's effects on endogenous KDM1A gene and LSD1 protein expressions were examined by qRT-PCR and western blot assays. NSCLC proliferation and migration were also examined by MTT proliferation and wound-scratch assays, respectively...
February 18, 2017: Biochimie
https://www.readbyqxmd.com/read/28186757/thieno-3-2-b-pyrrole-5-carboxamides-as-new-reversible-inhibitors-of-histone-lysine-demethylase-kdm1a-lsd1-part-2-structure-based-drug-design-and-structure-activity-relationship
#12
Paola Vianello, Luca Sartori, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Oronza A Botrugno, Paola Dessanti, Saverio Minucci, Stefania Vultaggio, Elisa Zagarrí, Mario Varasi, Ciro Mercurio
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors...
February 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28186755/thieno-3-2-b-pyrrole-5-carboxamides-as-new-reversible-inhibitors-of-histone-lysine-demethylase-kdm1a-lsd1-part-1-high-throughput-screening-and-preliminary-exploration
#13
Luca Sartori, Ciro Mercurio, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Stefania Vultaggio, Oronza A Botrugno, Paola Dessanti, Saverio Minucci, Elisa Zagarrí, Daniele Carettoni, Lucia Iuzzolino, Mario Varasi, Paola Vianello
Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2...
February 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28098854/lsd1-sustains-estrogen-driven-endometrial-carcinoma-cell-proliferation-through-the-pi3k-akt-pathway-via-di-demethylating-h3k9-of-cyclin%C3%A2-d1
#14
Chunqin Chen, Yanan Wang, Shiyu Wang, Yuan Liu, Jiawen Zhang, Yuyao Xu, Zhenbo Zhang, Wei Bao, Sufang Wu
A recent study reported that histone lysine specific demethylase 1 (LSD1, KDM1A) is overexpressed in endometrioid endometrial carcinoma (EEC) and associated with tumor progression as well as poor prognosis. However, the physiological function and mechanism of LSD1 in endometrial cancer (EC) remains largely unknown. In this study, we demonstrate that β-estradiol (E2) treatment increased LSD1 expression via the GPR30/PI3K/AKT pathway in endometrial cancer cells. Both siGPR30 and the PI3K inhibitor LY294002 block this effect...
March 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28069602/oncogenic-zeb2-activation-drives-sensitivity-toward-kdm1a-inhibition-in-t-cell-acute-lymphoblastic-leukemia
#15
Steven Goossens, Sofie Peirs, Wouter Van Loocke, Jueqiong Wang, Mina Takawy, Filip Matthijssens, Stefan E Sonderegger, Katharina Haigh, Thao Nguyen, Niels Vandamme, Magdaline Costa, Catherine Carmichael, Filip Van Nieuwerburgh, Dieter Deforce, Oded Kleifeld, David J Curtis, Geert Berx, Pieter Van Vlierberghe, Jody J Haigh
Elevated expression of the Zinc finger E-box binding homeobox transcription factor-2 (ZEB2) is correlated with poor prognosis and patient outcome in a variety of human cancer subtypes. Using a conditional gain-of-function mouse model, we recently demonstrated that ZEB2 is an oncogenic driver of immature T-cell acute lymphoblastic leukemia (T-ALL), a heterogenic subgroup of human leukemia characterized by a high incidence of remission failure or hematological relapse after conventional chemotherapy. Here, we identified the lysine-specific demethylase KDM1A as a novel interaction partner of ZEB2 and demonstrated that mouse and human T-ALLs with increased ZEB2 levels critically depend on KDM1A activity for survival...
February 23, 2017: Blood
https://www.readbyqxmd.com/read/27986293/neurolsd1-splicing-generated-epigenetic-enhancer-of-neuroplasticity
#16
REVIEW
Francesco Rusconi, Barbara Grillo, Emanuela Toffolo, Andrea Mattevi, Elena Battaglioli
The acquisition and maintenance of the specific neuronal functions underlying learning, memory, and emotion require transduction of environmental stimuli into remodeling of neuronal circuitry. This process occurs via induction of plasticity-related transcriptional programs. The epigenetic enzyme lysine-specific demethylase-1 (LSD1), also known as lysine demethylase 1A (KDM1A), and its neurospecific splicing variant neuroLSD1 have been implicated in this process through an antagonistic mechanism. Specifically, LSD1/neuroLSD1 are involved in the negative and positive regulation of activity-evoked transcription of immediate early genes (IEGs) impacting memory formation and emotional behavior...
January 2017: Trends in Neurosciences
https://www.readbyqxmd.com/read/27903753/a-novel-lsd1-inhibitor-t-3775440-disrupts-gfi1b-containing-complex-leading-to-transdifferentiation-and-impaired-growth-of-aml-cells
#17
Yoshinori Ishikawa, Kanae Gamo, Masato Yabuki, Shinji Takagi, Kosei Toyoshima, Kazuhide Nakayama, Akiko Nakayama, Megumi Morimoto, Hitoshi Miyashita, Ryo Dairiki, Yukiko Hikichi, Naoki Tomita, Daisuke Tomita, Shinichi Imamura, Misa Iwatani, Yusuke Kamada, Satoru Matsumoto, Ryujiro Hara, Toshiyuki Nomura, Ken Tsuchida, Kazuhide Nakamura
Dysregulation of the histone demethylase LSD1, also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here we describe the anti-leukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroleukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27893719/novel-kdm1a-inhibitors-induce-differentiation-and-apoptosis-of-glioma-stem-cells-via-unfolded-protein-response-pathway
#18
G R Sareddy, S Viswanadhapalli, P Surapaneni, T Suzuki, A Brenner, R K Vadlamudi
Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models...
April 27, 2017: Oncogene
https://www.readbyqxmd.com/read/27879268/transcriptional-selectivity-of-epigenetic-therapy-in-cancer
#19
Takahiro Sato, Matteo Cesaroni, Woonbok Chung, Shoghag Panjarian, Anthony Tran, Jozef Madzo, Yasuyuki Okamoto, Hanghang Zhang, Xiaowei Chen, Jaroslav Jelinek, Jean-Pierre J Issa
A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation, and ChIP-seq analyses the epigenetic response of a set of colon, breast, and leukemia cancer cell lines to small-molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343)...
January 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/27879032/altered-expression-of-brg1-and-histone-demethylases-and-aberrant-h3k4-methylation-in-less-developmentally-competent-embryos-at-the-time-of-embryonic-genome-activation
#20
Werner G Glanzner, Audrey Wachter, Ana Rita S Coutinho, Marcelo S Albornoz, Raj Duggavathi, Paulo B D GonÇAlves, Vilceu Bordignon
Epigenetics is a fundamental regulator underlying many biological functions, such as development and cell differentiation. Epigenetic modifications affect key chromatin regulation, including transcription and DNA repair, which are critical for normal embryo development. In this study, we profiled the expression of epigenetic modifiers and patterns of epigenetic changes in porcine embryos around the period of embryonic genome activation (EGA). We observed that Brahma-related gene 1 (BRG1) and Lysine demethylase 1A (KDM1A), which can alter the methylation status of lysine 4 in histone 3 (H3K4), localize to the nucleus at Day 3-4 of development...
November 23, 2016: Molecular Reproduction and Development
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