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https://www.readbyqxmd.com/read/28916652/lsd1-mediated-epigenetic-reprogramming-drives-cenpe-expression-and-prostate-cancer-progression
#1
Yi Liang, Musaddeque Ahmed, Haiyang Guo, Fraser Soares, Junjie T Hua, Shuai Gao, Catherine Lu, Christine Poon, Wanting Han, Jens Langstein, Muhammad B Ekram, Brian Li, Elai Davicioni, Mandeep Takhar, Nicholas Erho, R Jeffrey Karnes, Dianne Chadwick, Theodorus van der Kwast, Paul C Boutros, Cheryl H Arrowsmith, Felix Y Feng, Anthony Michael Joshua, Amina Zoubeidi, Changmeng Cai, Housheng H He
Androgen receptor (AR) signaling is a key driver of prostate cancer (PCa), and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant PCa (CRPC). Here we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell cycle genes including CENPE, a centromere binding protein and mitotic kinesin...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28912501/transcription-regulation-of-cdkn1a-p21-cip1-waf1-by-trf2-is-epigenetically-controlled-through-the-rest-repressor-complex
#2
Tabish Hussain, Dhurjhoti Saha, Gunjan Purohit, Anirban Kar, Anand Kishore Mukherjee, Shalu Sharma, Suman Sengupta, Parashar Dhapola, Basudeb Maji, Sreekanth Vedagopuram, Nobuko T Horikoshi, Nobuo Horikoshi, Raj K Pandita, Santanu Bhattacharya, Avinash Bajaj, Jean-François Riou, Tej K Pandita, Shantanu Chowdhury
We observed extra-telomeric binding of the telomere repeat binding factor TRF2 within the promoter of the cyclin-dependent kinase CDKNIA (p21/CIP1/WAF1). This result in TRF2 induced transcription repression of p21. Interestingly, p21 repression was through engagement of the REST-coREST-LSD1-repressor complex and altered histone marks at the p21 promoter in a TRF2-dependent fashion. Furthermore, mutational analysis shows p21 repression requires interaction of TRF2 with a p21 promoter G-quadruplex. Physiologically, TRF2-mediated p21 repression attenuated drug-induced activation of cellular DNA damage response by evading G2/M arrest in cancer cells...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28899795/microrna-137-and-its-downstream-target-lsd1-inversely-regulate-anesthetics-induced-neurotoxicity-in-dorsal-root-ganglion-neurons
#3
Lingyang Chen, Xiaodan Wang, Wenguang Huang, Tingting Ying, Minjuan Chen, Jianbin Cao, Mingcang Wang
PURPOSE: Anesthetic reagents, such as bupivacaine (Bv), induce significant neurotoxicity in dorsal root ganglion neurons (DRGNs). In this study, we investigated the expression, function and cross-association of microRNA-137-3p (miR-137-3p) and lysine (K)-specific demethylase 1A (LSD1) in a murine model of Bv-induced neural injury in DRGNs. METHODS: Murine DRGNs were culture in vitro and treated with Bv. QPCR was used to evaluate miR-137-3p expression in Bv-injured DRGNs...
September 9, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28892629/development-of-4-cyanophenyl-glycine-derivatives-as-reversible-inhibitors-of-lysine-specific-demethylase-1
#4
Daniel P Mould, Cristina Alli, Ulf Bremberg, Sharon Cartic, Allan M Jordan, Matthis Geitmann, Alba Maiques-Diaz, Alison E McGonagle, Tim C P Somervaille, Gary J Spencer, Fabrice Turlais, Donald J Ogilvie
Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukaemia (AML). Irreversible inhibitors developed from the non-specific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen, and subsequent in silico modelling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1)...
September 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28892104/synergistic-anti-aml-effects-of-the-lsd1-inhibitor-t-3775440-and-the-nedd8-activating-enzyme-inhibitor-pevonedistat-via-transdifferentiation-and-dna-rereplication
#5
Y Ishikawa, K Nakayama, M Morimoto, A Mizutani, A Nakayama, K Toyoshima, A Hayashi, S Takagi, R Dairiki, H Miyashita, S Matsumoto, K Gamo, T Nomura, K Nakamura
Lysine-specific demethylase 1A (LSD1, KDM1A) specifically demethylates di- and monomethylated histones H3K4 and K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation...
September 11, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28878246/loss-of-nr2e3-represses-ahr-by-lsd1-reprogramming-is-associated-with-poor-prognosis-in-liver-cancer
#6
Tilak Khanal, Kwangmin Choi, Yuet-Kin Leung, Jiang Wang, Dasom Kim, Vinothini Janakiram, Sung-Gook Cho, Alvaro Puga, Shuk-Mei Ho, Kyounghyun Kim
The aryl hydrocarbon receptor (AHR) plays crucial roles in inflammation, metabolic disorder, and cancer. However, the molecular mechanisms regulating AHR expression remain unknown. Here, we found that an orphan nuclear NR2E3 maintains AHR expression, and forms an active transcriptional complex with transcription factor Sp1 and coactivator GRIP1 in MCF-7 human breast and HepG2 liver cancer cell lines. NR2E3 loss promotes the recruitment of LSD1, a histone demethylase of histone 3 lysine 4 di-methylation (H3K4me2), to the AHR gene promoter region, resulting in repression of AHR expression...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28860622/lsd1-modulates-the-non-canonical-integrin-%C3%AE-3-signaling-pathway-in-non-small-cell-lung-carcinoma-cells
#7
So-Young Lim, Iris Macheleidt, Priya Dalvi, Stephan C Schäfer, Martin Kerick, Luka Ozretić, Sandra Ortiz-Cuaran, Julie George, Sabine Merkelbach-Bruse, Jürgen Wolf, Bernd Timmermann, Roman K Thomas, Michal R Schweiger, Reinhard Buettner, Margarete Odenthal
The epigenetic writer lysine-specific demethylase 1 (LSD1) is aberrantly upregulated in many cancer types and its overexpression correlates with poor survival and tumor progression. In this study, we analysed LSD1 function in non-small cell lung cancer adenocarcinomas. Expression profiling of 182 cases of lung adenocarcinoma proved a significant correlation of LSD1 overexpression with lung adenocarcinoma progression and metastasis. KRAS-mutated lung cancer cell clones were stably silenced for LSD1 expression...
August 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28858731/lncrna-fezf1-as1-enhances-epithelial-mesenchymal-transition-emt-through-suppressing-e-cadherin-and-regulating-wnt-pathway-in-non-small-cell-lung-cancer-nsclc
#8
Rong He, Fei Hu Zhang, Ning Shen
OBJECTIVE: Recent discoveries verify that long non-coding RNAs (lncRNAs) are important functional regulators involved in non-small cell lung cancer (NSCLC) progression. However, long non-coding RNA FEZF1-AS1 was not been investigated in NSCLC so for. METHODS: We applied the quantitative real time polymerase chain reaction (qRT-PCR) assays to detect the expression of lncRNA FEZF1-AS1 in NSCLC tissues and adjacent normal tissues. Cell proliferation and invasion capacities were evaluated by MTT, colony formation, and cell invasion assays...
August 28, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28843610/role-of-the-dna-repair-glycosylase-ogg1-in-the-activation-of-murine-splenocytes
#9
Marco Seifermann, Alexander Ulges, Tobias Bopp, Svetlana Melcea, Andrea Schäfer, Sugako Oka, Yusaku Nakabeppu, Arne Klungland, Christof Niehrs, Bernd Epe
OGG1 (8-oxoguanine-DNA glycosylase) is the major DNA repair glycosylase removing the premutagenic DNA base modification 8-oxo-7,8-dihydroguanine (8-oxoG) from the genome of mammalian cells. In addition, there is accumulating evidence that OGG1 and its substrate 8-oxoG might function in the regulation of certain genes, which could account for an attenuated immune response observed in Ogg1(-/-) mice in several settings. Indications for at least two different mechanisms have been obtained. Thus, OGG1 could either act as an ancillary transcription factor cooperating with the lysine-specific demethylase LSD1 or as an activator of small GTPases...
August 12, 2017: DNA Repair
https://www.readbyqxmd.com/read/28832116/chemically-sumoylated-histone-h4-stimulates-intranucleosomal-demethylation-by-the-lsd1-corest-complex
#10
Abhinav Dhall, Caroline E Weller, Aurea Chu, Patrick M M Shelton, Champak Chatterjee
Lysine-specific demethylase 1 (LSD1) downregulates eukaryotic gene activity by demethylating mono- and dimethylated Lys4 in histone H3. Elucidating the biochemical crosstalk of LSD1 with histone post-translational modifications (PTMs) is essential for developing LSD1-targeted therapeutics in human cancers. We interrogated the small ubiquitin-like modifier (SUMO)-driven regulation of LSD1 activity with semisynthetic nucleosomes containing site-specifically methylated and sumoylated histones. We discovered that nucleosomes containing sumoylated histone H4 (suH4), a modification associated with gene repression, stimulate LSD1 activity by a mechanism dependent upon the SUMO-interaction motif in CoREST...
August 30, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28811844/lsd1-dual-function-in-mediating-epigenetic-corruption-of-the-vitamin-d-signaling-in-prostate-cancer
#11
Sebastiano Battaglia, Ellen Karasik, Bryan Gillard, Jennifer Williams, Trisha Winchester, Michael T Moser, Dominic J Smiraglia, Barbara A Foster
BACKGROUND: Lysine-specific demethylase 1A (LSD1) is a key regulator of the androgen (AR) and estrogen receptors (ER), and LSD1 levels correlate with tumor aggressiveness. Here, we demonstrate that LSD1 regulates vitamin D receptor (VDR) activity and is a mediator of 1,25(OH)2-D3 (vitamin D) action in prostate cancer (PCa). METHODS: Athymic nude mice were xenografted with CWR22 cells and monitored weekly after testosterone pellet removal. Expression of LSD1 and VDR (IHC) were correlated with tumor growth using log-rank test...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28801480/gfi1-functions-in-transcriptional-control-and-cell-fate-determination-require-snag-domain-methylation-to-recruit-lsd1
#12
Matthew Velinder, Jason Singer, Diana Bareyan, Jessica Meznarich, Christopher M Tracy, James M Fulcher, David McClellan, Helena Lucente, Sarah Franklin, Sunil Sharma, Michael E Engel
No abstract text is available yet for this article.
August 11, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28800922/inhibition-of-h3k4-demethylation-induces-autophagy-in-cancer-cell-lines
#13
Zhen Wang, Qiao-Yun Long, Lin Chen, Jia-Dong Fan, Zhao-Ning Wang, Lian-Yun Li, Min Wu
Epigenetic factors and related small molecules have emerged to be strongly involved in autophagy process. Here we report that 2-PCPA and GSK-LSD1, two inhibitors of histone H3K4 demethylase KDM1A/LSD1, induce autophagy in multiple mammalian cell lines. The two small molecules induce accumulation of LC3II, formation of autophagosome and autolysosome, and SQSTM1/p62 degradation. 2-PCPA treatment inhibits cell proliferation through cell cycle arrest but does not inducing cell death. Exogenous expression of KDM1A/LSD1 impaired the autophagic phenotypes triggered by 2-PCPA...
August 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28783174/lysine-specific-demethylase-lsd1-regulates-autophagy-in-neuroblastoma-through-sesn2-dependent-pathway
#14
S Ambrosio, C D Saccà, S Amente, S Paladino, L Lania, B Majello
Autophagy is a physiological process, important for recycling of macromolecules and maintenance of cellular homeostasis. Defective autophagy is associated with tumorigenesis and has a causative role in chemotherapy resistance in leukemia and in solid cancers. Here, we report that autophagy is regulated by the lysine-specific demethylase LSD1/KDM1A, an epigenetic marker whose overexpression is a feature of malignant neoplasia with an instrumental role in cancer development. In the present study, we determine that two different LSD1 inhibitors (TCP and SP2509) as well as selective ablation of LSD1 expression promote autophagy in neuroblastoma cells...
August 7, 2017: Oncogene
https://www.readbyqxmd.com/read/28778066/inhibition-of-lsd1-epigenetically-attenuates-oral-cancer-growth-and-metastasis
#15
Saqer F Alsaqer, Mustafa M Tashkandi, Vinay K Kartha, Ya-Ting Yang, Yazeed Alkheriji, Andrew Salama, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti, Manish V Bais
Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase and a member of the amine oxidase (AO) family. LSD1 is a flavin-containing AO that specifically catalyzes the demethylation of mono- and di-methylated histone H3 lysine 4 through an FAD-dependent oxidative reaction. LSD1 is inappropriately upregulated in lung, liver, brain and esophageal cancers, where it promotes cancer initiation, progression, and metastasis. However, unlike other lysine-specific demethylases, the role and specific targets of LSD1 in oral squamous cell carcinoma (OSCC) pathogenesis remain unknown...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28753574/functional-characterization-of-lysine-specific-demethylase-2-lsd2-kdm1b-in-breast-cancer-progression
#16
Lin Chen, Shauna N Vasilatos, Ye Qin, Tiffany A Katz, Chunyu Cao, Hao Wu, Nilgun Tasdemir, Kevin M Levine, Steffi Oesterreich, Nancy E Davidson, Yi Huang
Flavin-dependent histone demethylases govern histone H3K4 methylation and act as important chromatin modulators that are extensively involved in regulation of DNA replication, gene transcription, DNA repair, and heterochromatin gene silencing. While the activities of lysine-specific demethylase 1 (LSD1/KDM1A) in facilitating breast cancer progression have been well characterized, the roles of its homolog LSD2 (KDM1B) in breast oncogenesis are relatively less understood. In this study, we showed that LSD2 protein level was significantly elevated in malignant breast cell lines compared with normal breast epithelial cell line...
July 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28722477/advances-toward-lsd1-inhibitors-for-cancer-therapy
#17
Xiaoli Fu, Peng Zhang, Bin Yu
LSD1 has become an important biologically validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and inactivation by small molecules suppresses cancer cell differentiation, proliferation, invasion and migration. To date, a large number of LSD1 inhibitors have been reported, RG6016, GSK-2879552, INCB059872, IMG-7289 and CC-90011 are currently undergoing clinical assessment for the treatment of acute myeloid leukemia, small-cell lung cancer, etc...
July 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28722470/novel-potent-inhibitors-of-the-histone-demethylase-kdm1a-lsd1-orally-active-in-a-murine-promyelocitic-leukemia-model
#18
Paolo Trifirò, Anna Cappa, Silvia Brambillasca, Oronza A Botrugno, Maria Rosaria Cera, Roberto Dal Zuffo, Paola Dessanti, Giuseppe Meroni, Florian Thaler, Manuela Villa, Saverio Minucci, Ciro Mercurio, Mario Varasi, Paola Vianello
BACKGROUND: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor...
July 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28720390/epigenetic-regulation-of-epithelial-to-mesenchymal-transition-by-the-lysine-specific-demethylase-lsd1-kdm1a
#19
REVIEW
Susanna Ambrosio, Carmen D Saccà, Barbara Majello
The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. LSD1 regulates the epithelial mesenchymal transition (EMT) in epithelial cells, i.e., the ability to transition into mesenchymal cells, to lose homotypic adhesion and to acquire migratory capacity. From its initial discovery as a component of the Snail complex, multiple studies highlighted the causative role of LSD1 in cell invasiveness and EMT, describing its direct involvement in different molecular processes through the interaction with specific partners...
July 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28717007/epigenetic-suppression-of-human-telomerase-htert-is-mediated-by-the-metastasis-suppressor-nme2-in-a-g-quadruplex-dependent-fashion
#20
Dhurjhoti Saha, Ankita Singh, Tabish Hussain, Vivek Srivastava, Suman Sengupta, Anirban Kar, Parashar Dhapola, Vishnu Dhople, Ramesh Ummani, Shantanu Chowdhury
Transcriptional activation of the human telomerase reverse transcriptase (hTERT) gene, which remains repressed in adult somatic cells, is critical during tumorigenesis. Several transcription factors and the epigenetic state of the hTERT promoter are known to be important for tight control of hTERT in normal tissues, but the molecular mechanisms leading to hTERT reactivation in cancer are not well understood. Surprisingly, here we found occupancy of the metastasis suppressor nonmetastatic 2 (NME2) within hTERT core promoter in HT1080 fibrosarcoma cells and HCT116 colon cancer cells, and NME2 mediated transcriptional repression of hTERT in these cells...
July 17, 2017: Journal of Biological Chemistry
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