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https://www.readbyqxmd.com/read/28722477/advances-toward-lsd1-inhibitors-for-cancer-therapy
#1
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
#2
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
#3
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
#4
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
https://www.readbyqxmd.com/read/28700271/lsd1-a-metabolic-sensor-of-environment-requirements-that-prevents-adipose-tissue-from-aging
#5
Delphine Duteil, Milica Tosic, Roland Schüle
Understanding development and maintenance of beige adipocytes provide exciting insights in establishing novel therapies against obesity and obesity-associated disorders. Lysine-specific demethylase 1 (Lsd1) is an epigenetic eraser required for differentiation and function of adipocytes. Lsd1 is involved in early commitment of preadipocytes, but dispensable for terminal differentiation of white adipose tissue (WAT). In mature adipocytes, Lsd1 responds to different environmental stimuli to alter metabolic function and enable proper thermogenic and oxidative response...
June 26, 2017: Adipocyte
https://www.readbyqxmd.com/read/28699367/a-comprehensive-review-of-lysine-specific-demethylase-1-and-its-roles-in-cancer
#6
Amir Hosseini, Saverio Minucci
Histone methylation plays a key role in the regulation of chromatin structure, and its dynamics regulates important cellular processes. The investigation of the role of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Lysine-specific demethylase 1(LSD1, also known as KDM1A) is the first discovered histone lysine demethylase, with the ability to demethylase H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner...
July 12, 2017: Epigenomics
https://www.readbyqxmd.com/read/28687800/pkc%C3%AE-mediated-phosphorylation-of-lsd1-is-required-for-presynaptic-plasticity-and-hippocampal-learning-and-memory
#7
Chae-Seok Lim, Hye Jin Nam, Jaehyun Lee, Dongha Kim, Ja Eun Choi, SukJae Joshua Kang, Somi Kim, Hyopil Kim, Chuljung Kwak, Kyu-Won Shim, Siyong Kim, Hyoung-Gon Ko, Ro Un Lee, Eun-Hae Jang, Juyoun Yoo, Jaehoon Shim, Md Ariful Islam, Yong-Seok Lee, Jae-Hyung Lee, Sung Hee Baek, Bong-Kiun Kaang
Lysine-specific demethylase 1 (LSD1) is a histone demethylase that participates in transcriptional repression or activation. Recent studies reported that LSD1 is involved in learning and memory. Although LSD1 phosphorylation by PKCα was implicated in circadian rhythmicity, the importance of LSD1 phosphorylation in learning and memory is unknown. In this study, we examined the roles of LSD1 in synaptic plasticity and memory using Lsd1 (SA/SA) knock-in (KI) mice, in which a PKCα phosphorylation site is mutated...
July 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28667074/lsd1-inhibitor-t-3775440-inhibits-sclc-cell-proliferation-by-disrupting-lds1-interactions-with-snag-domain-proteins-insm1-and-gfi1b
#8
Shinji Takagi, Yoshinori Ishikawa, Akio Mizutani, Shinji Iwasaki, Satoru Matsumoto, Yusuke Kamada, Toshiyuki Nomura, Kazuhide Nakamura
T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1, which exerts anti-proliferative effects by disrupting the interaction between LSD1 and GFI1B, a SNAG domain transcription factor, inducing leukemia cell transdifferentiation. Here we describe the anti-cancer effects and mechanism of action of T-3775440 in small cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo T-3775440 disrupted the interaction between LSD1 and the transcriptional repressor INSM1, thereby inhibiting expression of neuroendocrine-associated genes such as ASCL1...
June 30, 2017: Cancer Research
https://www.readbyqxmd.com/read/28661483/gene-knockout-of-zmym3-in-mice-arrests-spermatogenesis-at-meiotic-metaphase-with-defects-in-spindle-assembly-checkpoint
#9
Xiangjing Hu, Bin Shen, Shangying Liao, Yan Ning, Longfei Ma, Jian Chen, Xiwen Lin, Daoqin Zhang, Zhen Li, Chunwei Zheng, Yanmin Feng, Xingxu Huang, Chunsheng Han
ZMYM3, a member of the MYM-type zinc finger protein family and a component of a LSD1-containing transcription repressor complex, is predominantly expressed in the mouse brain and testis. Here, we show that ZMYM3 in the mouse testis is expressed in somatic cells and germ cells until pachytene spermatocytes. Knockout (KO) of Zmym3 in mice using the CRISPR-Cas9 system resulted in adult male infertility. Spermatogenesis of the KO mice was arrested at the metaphase of the first meiotic division (MI). ZMYM3 co-immunoprecipitated with LSD1 in spermatogonial stem cells, but its KO did not change the levels of LSD1 or H3K4me1/2 or H3K9me2...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28642444/upregulation-of-cd11b-and-cd86-through-lsd1-inhibition-promotes-myeloid-differentiation-and-suppresses-cell-proliferation-in-human-monocytic-leukemia-cells
#10
Jianwu Fang, Haiyan Ying, Ting Mao, Yanjia Fang, Yuan Lu, He Wang, Irene Zang, Zhaofu Wang, Ying Lin, Mengxi Zhao, Xiao Luo, Zongyao Wang, Yan Zhang, Chao Zhang, Wei Xiao, Yan Wang, Wei Tan, Zhui Chen, Chris Lu, Peter Atadja, En Li, Kehao Zhao, Jianfeng Liu, Justin Gu
LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells...
June 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28634230/similarity-in-gene-regulatory-networks-suggests-that-cancer-cells-share-characteristics-of-embryonic-neural-cells
#11
Zan Zhang, Anhua Lei, Liyang Xu, Lu Chen, Yonglong Chen, Xuena Zhang, Yan Gao, Xiaoli Yang, Min Zhang, Ying Cao
Cancer cells are immature cells resulting from cellular reprogramming by gene misregulation, and re-differentiation is expected to reduce malignancy. It is unclear, however, whether cancer cells can undergo terminal differentiation. Here, we show that, inhibition of the epigenetic modification enzymes enhancer of zeste homolog 2 (EZH2), histone deacetylases (HDACs) 1 and 3, lysine demethylase 1A (LSD1), or DNA methyltransferase 1 (DNMT1), which all promote cancer development and progression, leads to postmitotic neuron-like differentiation with loss of malignant features in distinct solid cancer cell lines...
June 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28627608/silencing-of-lsd1-gene-modulates-histone-methylation-and-acetylation-and-induces-the-apoptosis-of-jeko-1-and-molt-4-cells
#12
Zhong-Kai Zou, Yi-Qun Huang, Yong Zou, Xu-Ke Zheng, Xu-Dong Ma
Lysine-specific demethylase 1 (LSD1) has been identified and biochemically characterized in epigenetics; however, the pathological roles of its dysfunction in mantle cell lymphoma (MCL) and T-cell acute lymphoblastic leukemia remain to be elucidated. In this study, we evaluated LSD1, and histone H3 lysine 4 (H3K4)me1 and H3K4me2 expression in patients with MCL and silenced LSD1 in JeKo‑1 and MOLT‑4 cells, in order to define its role in JeKo‑1 and MOLT‑4 cell proliferation and apoptosis. We retrospectively analyzed the protein expression of LSD1, and mono- and dimethylated H3K4 (H3K4me1 and H3K4me2), and cyclin D1 and Ki67 in 30 cases of MCL by immunohistochemistry...
June 19, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28617441/concomitant-epigenetic-targeting-of-lsd1-and-hdac-synergistically-induces-mitochondrial-apoptosis-in-rhabdomyosarcoma-cells
#13
Tinka Haydn, Eric Metzger, Roland Schuele, Simone Fulda
The lysine-specific demethylase 1 (LSD1) is overexpressed in several cancers including rhabdomyosarcoma (RMS). However, little is yet known about whether or not LSD1 may serve as therapeutic target in RMS. We therefore investigated the potential of LSD1 inhibitors alone or in combination with other epigenetic modifiers such as histone deacetylase (HDAC) inhibitors. Here, we identify a synergistic interaction of LSD1 inhibitors (i.e., GSK690, Ex917) and HDAC inhibitors (i.e., JNJ-26481585, SAHA) to induce cell death in RMS cells...
June 15, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28610981/3d-qsar-comfa-comsia-molecular-docking-and-molecular-dynamics-simulations-study-of-6-aryl-5-cyano-pyrimidine-derivatives-to-explore-the-structure-requirements-of-lsd1-inhibitors
#14
Lina Ding, Zhi-Zheng Wang, Xu-Dong Sun, Jing Yang, Chao-Ya Ma, Wen Li, Hong-Min Liu
Recently, Histone Lysine Specific Demethylase 1 (LSD1) was regarded as a promising anticancer target for the novel drug discovery. And several small molecules as LSD1 inhibitors in different structures have been reported. In this work, we carried out a molecular modeling study on the 6-aryl-5-cyano-pyrimidine fragment LSD1 inhibitors using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28601046/lsd1-knockdown-reveals-novel-histone-lysine-methylation-in-human-breast-cancer-mcf-7-cells
#15
Yue Jin, Bo Huo, Xueqi Fu, Zhongyi Cheng, Jun Zhu, Yu Zhang, Tian Hao, Xin Hu
Histone lysine methylation, which plays an important role in the regulation of gene expression, genome stability, chromosome conformation and cell differentiation, is a dynamic process that is collaboratively regulated by lysine methyltransferases (KMTs) and lysine demethylases (KDMs). LSD1, the first identified KDMs, catalyzes the demethylation of mono- and di-methylated H3K4 and H3K9. Here, we systematically investigated the effects of LSD1 knockdown on histone methylations. Surprisingly, in addition to H3K4 and H3K9, the methylation level on other histone lysines, such as H3K27, H3K36 and H3K79, are also increased...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28597915/dissecting-lsd1-dependent-neuronal-maturation-in-the-olfactory-epithelium
#16
Julie H Coleman, Brian Lin, James E Schwob
Neurons in the olfactory epithelium (OE) each express a single dominant olfactory receptor (OR) allele from among roughly 1000 different OR genes. While monogenic and monoallelic OR expression has been appreciated for over two decades, regulators of this process are still being described; most recently, epigenetic modifiers have been of high interest as silent OR genes are decorated with transcriptionally-repressive trimethylated histone 3 lysine 9 (H3K9me3) whereas active OR genes are decorated with transcriptionally-activating trimethylated histone 3 lysine 4 (H3K4me3)...
June 9, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28584023/notch-represses-transcription-by-prc2-recruitment-to-the-ternary-complex
#17
Xiaoqing Han, Prathibha Ranganathan, Christos Tzimas, Kelly L Weaver, Ke Jin, Luisana Astudillo, Wen Zhou, Xiaoxia Zhu, Bin Li, David J Robbins, Anthony J Capobianco
It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner...
June 5, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28571892/lpe-1-an-orally-active-pyrimidine-derivative-inhibits-growth-and-mobility-of-human-esophageal-cancers-by-targeting-lsd1
#18
Bo Wang, Bing Zhao, Lu-Ping Pang, Yuan-Di Zhao, Qian Guo, Jun-Wei Wang, Yi-Chao Zheng, Xin-Hui Zhang, Ying Liu, Guang-Yao Liu, Wen-Ge Guo, Chao Wang, Zhong-Hua Li, Xue-Jing Mao, Bin Yu, Li-Ying Ma, Hong-Min Liu
Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC50=0...
May 30, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28555890/the-dual-role-of-lesion-simulating-disease-1-as-a-condition-dependent-scaffold-protein-and-transcription-regulator
#19
Weronika Czarnocka, Katrien Van Der Kelen, Patrick Willems, Magdalena Szechynska-Hebda, Sara Shahnejat-Bushehri, Salma Balazadeh, Anna Rusaczonek, Bernd Mueller-Roeber, Frank Van Breusegem, Stanisław Karpinski
Since its discovery over two decades ago as an important cell death regulator in Arabidopsis thaliana, the role of LESION SIMULATING DISEASE 1 (LSD1) has been studied intensively within both biotic and abiotic stress responses as well as with respect to plant fitness regulation. However, its molecular mode of action remains enigmatic. Here we demonstrate that nucleo-cytoplasmic LSD1 interacts with a broad range of other proteins that are engaged in various molecular pathways such as ubiquitination, methylation, cell cycle control, gametogenesis, embryo development and cell wall formation...
May 27, 2017: Plant, Cell & Environment
https://www.readbyqxmd.com/read/28550687/tanshinone-suppresses-arecoline-induced-epithelial-mesenchymal-transition-in-oral-submucous-fibrosis-by-epigenetically-reactivating-the-p53-pathway
#20
Lian Zheng, Zhen-Jie Guan, Wen-Ting Pan, Tian-Fang Du, Yu-Jia Zhai, Jia Guo
Oral submucous fibrosis (OSF) induced by the chewing of areca nut has been considered as a precancerous lesion with a higher probability of developing oral squamous cell carcinoma. Tanshinone (TSN) is the main component extracted from Salvia miltiorrhiza, a traditional Chinese medicine, which was found to have diverse pharmacological effects such as anti-inflammatory and anti-tumor effects. In current study, we aim to identify inhibitory effects and the underlying mechanism of Tanshinone on OSF progress. We found that treatment of TSN inhibited arecoline-mediated proliferation of primary human oral mucosal fibroblasts, and reversed the promotive effects of arecoline on EMT process...
May 21, 2017: Oncology Research
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