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lysine demethylase

Ye Qin, Shauna N Vasilatos, Lin Chen, Hao Wu, Zhishen Cao, Yumei Fu, Min Huang, Anda M Vlad, Binfeng Lu, Steffi Oesterreich, Nancy E Davidson, Yi Huang
Immunotherapy strategies have been emerging as powerful weapons against cancer. Early clinical trials reveal that overall response to immunotherapy is low in breast cancer patients, suggesting that effective strategies to overcome resistance to immunotherapy are urgently needed. In this study, we investigated whether epigenetic reprograming by modulating histone methylation could enhance effector T lymphocyte trafficking and improve therapeutic efficacy of immune checkpoint blockade in breast cancer with focus on triple-negative breast cancer (TNBC) subtype...
August 15, 2018: Oncogene
Fei-Ran Han, Xuan-Min Guang, Qiu-Hong Wan, Sheng-Guo Fang
The giant panda (Ailuropoda melanoleuca) is popular around the world and is widely recognised as a symbol of nature conservation. A draft genome of the giant panda is now available, but its Y chromosome has not been sequenced. Y chromosome data is necessary for study of sex chromosome evolution, male development, and spermatogenesis. Thus, in the present study, we sequenced two parts of the giant panda Y chromosome utilizing a male giant panda fosmid library. The sequencing data was assembled into two contigs, each ∼100 kb in length with no gaps, providing high-quality resources for studying the giant panda Y chromosome...
August 13, 2018: Genome Biology and Evolution
Yu Liu, Deyu Zhou, Di Qi, Jiabin Feng, Zhou Liu, Yue Hu, Wenyuan Shen, Chang Liu, Xiaohong Kong
Despite the notable success of combination antiretroviral therapy, how to eradicate latent HIV-1 from reservoirs poses a challenge. The Tat protein plays an indispensable role in HIV reactivation and histone demethylase LSD1 promotes Tat-mediated long terminal repeats (LTR) activation. However, the role of LSD1 in remodeling chromatin and the role of its component BHC80 in activation of latent HIV-1 in T cells are unknown. Our findings indicate that LSD1 could decrease the level of histone H3 lysine 4 trimethylation (H3K4me3) at the HIV-1 promoter by recruiting histone lysine demethylase 5A (KDM5A) and preventing histone methyltransferase Set1A and WD-40 repeat protein 5 (WDR5) from binding to LTR...
August 13, 2018: Virus Genes
Michael Leshets, Yardena B H Silas, Norbert Lehming, Ophry Pines
Fumarase is an enzyme of the tricarboxylic acid (TCA) cycle in mitochondria, but in recent years, it has emerged as a participant in the response to DNA double strand breaks (DSBs) in the nucleus. In fact, this enzyme is dual-targeted and can be also readily detected in the mitochondrial and cytosolic/nuclear compartments of all the eukaryotic organisms examined. Intriguingly, this evolutionary conserved cytosolic population of fumarase, its enzymatic activity and the associated metabolite fumarate, are required for the cellular DNA damage response (DDR) to double-strand breaks...
2018: Frontiers in Molecular Biosciences
Jeison Garcia, Fernando Lizcano
Members of the jumonji-containing lysine demethylase protein family have been associated with cancer development, although their specific roles in the evolution of tumor cells remain unknown. This work examines the effects of lysine demethylase 4C (KDM4C) knockdown on the behavior of a triple-negative breast cancer cell line. KDM4C expression was knocked-down by siRNA and analyzed by Western blot and immunofluorescence. HCC38 cell proliferation was examined by MTT assay, while breast cancer cells' migration and invasion were tested in Transwell format by chemotaxis...
2018: Breast Cancer: Basic and Clinical Research
Lizhen Wu, Jian Cao, Wesley L Cai, Sabine M Lang, John R Horton, Daniel J Jansen, Zongzhi Z Liu, Jocelyn F Chen, Meiling Zhang, Bryan T Mott, Katherine Pohida, Ganesha Rai, Stephen C Kales, Mark J Henderson, Xin Hu, Ajit Jadhav, David J Maloney, Anton Simeonov, Shu Zhu, Akiko Iwasaki, Matthew D Hall, Xiaodong Cheng, Gerald S Shadel, Qin Yan
Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases...
August 6, 2018: PLoS Biology
HaEun Kim, Yoon Jung Park
Cancer metabolism is considered as one of major cancer hallmarks. It is important to understand cancer-specific metabolic changes and its impact on cancer biology to identify therapeutic potentials. Among cancer-specific metabolic changes, a role of serine metabolism has been discovered in various cancer types. Upregulation of serine synthesis pathway (SSP) supports cell proliferation and metastasis. The change of serine metabolism is, in part, mediated by epigenetic modifiers, such as Euchromatic histone-lysine N-methyltransferase 2 and Lysine Demethylase 4C...
July 2018: Clinical Nutrition Research
(no author information available yet)
Transient site-specific DNA copy-number gains (TSSG) are controlled by histone lysine methylation dynamics.
August 3, 2018: Cancer Discovery
Daniela Magliulo, Rosa Bernardi, Samantha Messina
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy characterized by the accumulation of incompletely differentiated progenitor cells (blasts) in the bone marrow and blood, and by suppression of normal hematopoiesis. It has recently become apparent that the AML genome is characterized by recurrent mutations and dysregulations in epigenetic regulators. These mutations frequently occur before the onset of full blown leukemia, at the pre-leukemic phase, and persist in residual disease that remains after therapeutic intervention, thus suggesting that targeting the AML epigenome may help to eradicate minimal residual disease and prevent relapse...
2018: Frontiers in Oncology
Hung-Jung Wang, Mamata Pochampalli, Ling-Yu Wang, June X Zou, Pei-Shan Li, Sheng-Chieh Hsu, Bi-Juan Wang, Shih-Han Huang, Ping Yang, Joy C Yang, Cheng-Ying Chu, Chia-Ling Hsieh, Shian-Ying Sung, Chien-Feng Li, Clifford G Tepper, David K Ann, Allen C Gao, Christopher P Evans, Yoshihiro Izumiya, Chi-Pin Chuu, Wen-Ching Wang, Hong-Wu Chen, Hsing-Jien Kung
During the evolution into castration or therapy resistance, prostate cancer cells reprogram the androgen responses to cope with the diminishing level of androgens, and undergo metabolic adaption to the nutritionally deprived and hypoxia conditions. AR (androgen receptor) and PKM2 (pyruvate kinase M2) have key roles in these processes. We report in this study, KDM8/JMJD5, a histone lysine demethylase/dioxygnase, exhibits a novel property as a dual coactivator of AR and PKM2 and as such, it is a potent inducer of castration and therapy resistance...
August 2, 2018: Oncogene
Angela Rivers, Ramasamy Jagadeeswaran, Donald Lavelle
Sickle cell disease (SCD) is caused by a mutation of the b-globin gene(21) that triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the U.S. and millions worldwide(53) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy(60, 70). Hematopoietic stem cell (HSC) transplantation can be curative, but the majority of patients do not have a suitable donor (80). Advanced gene editing technologies also offer the possibility of a cure (16, 34), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote...
August 1, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Tomáš Vacík, Dijana Lađinović, Ivan Raška
Aberrant levels of histone modifications lead to chromatin malfunctioning and consequently to various developmental defects and human diseases. Therefore, the proteins bearing the ability to modify histones have been extensively studied and the molecular mechanisms of their action are now fairly well understood. However, little attention has been paid to naturally occurring alternative isoforms of chromatin modifying proteins and to their biological roles. In this review, we focus on mammalian KDM2A and KDM2B, the only two lysine demethylases whose genes have been described to produce also an alternative isoform lacking the N-terminal demethylase domain...
July 30, 2018: Nucleus
Sweta Mishra, Capucine Van Rechem, Sangita Pal, Thomas L Clarke, Damayanti Chakraborty, Sarah D Mahan, Joshua C Black, Michael S Lawrence, Danette L Daniels, Johnathan R Whetstine
Acquired chromosomal DNA amplifications are features of many tumors. Although overexpression and stabilization of the histone H3 lysine 9/36 (H3K9/36) tri-demethylase KDM4A generates transient site-specific copy number gains (TSSGs), additional mechanisms directly controlling site-specific DNA copy gains are not well defined. In this study, we uncover a collection of H3K4-modifying chromatin regulators that function with H3K9 and H3K36 regulators to orchestrate TSSGs. Specifically, the H3K4 tri-demethylase KDM5A and specific COMPASS/KMT2 H3K4 methyltransferases modulate different TSSG loci through H3K4 methylation states and KDM4A recruitment...
August 9, 2018: Cell
Lucia Guillade, Federica Sarno, Hanna Tarhnskaya, Angela Nebbioso, Susana Alvarez, Akane Kawamura, Christopher Schofield, Lucia Altucci, Angel R de Lera
The natural product tripartin has been reported to inhibit the N-methyl lysine histone demethylase KDM4A. A synthesis of tripartin starting from 3,5-dimethoxyphenylacrylic acid was developed and the enantiomers were separated by chiral HPLC. We observed that both tripartin enantiomers manifested an apparent increase in the H3K9me3 levels when dosed in cells, as measured by Western blot analysis. Thus, there is no enantiomeric discrimination towards this natural product in terms of its effects on cellular histone methylation status...
July 26, 2018: ChemMedChem
Hanna Tarhonskaya, Anthony Tumber, Akane Kawamura, Christopher J Schofield
Histone modifications, including lysine methylation marks on histone tails, modulate the accessibility of genes for transcription. Changes in histone tail methylation patterns can cause transcriptional activation or repression. The dynamic regulation of lysine methylation patterns is enabled by two distinct groups of enzymes: histone methyltransferases (KMTs) and demethylases (KDMs). The Jumonji C (JmjC) domain-containing lysine histone demethylases (JmjC-KDMs) alter the methylation levels of histone tails by removing tri-, di-, or mono-methylation marks...
March 2018: Current Protocols in Pharmacology
Kokiladevi Alagarswamy, Ken-Ichi Shinohara, Shihori Takayanagi, Masaki Fukuyo, Atsushi Okabe, Bahityar Rahmutulla, Natsumi Yoda, Rui Qin, Naoki Shiga, Masahiro Sugiura, Hiroaki Sato, Kazuko Kita, Takayoshi Suzuki, Tetsuhiro Nemoto, Atsushi Kaneda
Epigenome regulates gene expression to determine cell fate, and accumulation of epigenomic aberrations leads to diseases, including cancer. NCD38 inhibits lysine-specific demethylase-1 (LSD1), a histone demethylase targeting H3K4me1 and H3K4me2, but not H3K4me3. In this study, we conjugated NCD38 with a potent small molecule called pyrrole (Py) imidazole (Im) polyamide, to analyze whether targets of the inhibitor could be regulated in a sequence-specific manner. We synthesized two conjugates using β-Ala (β) as a linker, i...
June 29, 2018: Oncotarget
Feifei Peng, Xiaoli Shi, Yin Meng, Bo Dong, Guangchi Xu, Tingting Hou, Yang Shi, Tao Liu
Renal cell carcinoma (RCC) is one of the most aggressive malignancies with increasing incidence worldwide and is characterized by dismal prognosis owing to a lack of early detection and prognostic biomarkers for this fatal disease. Accumulating studies demonstrated that abnormally expressed long non-coding RNAs (lncRNAs) are involved in tumorigenesis and progression. Specifically, HOTTIP is upregulated and exerts oncogenic properties in some cancers. However, its clinical significance, biological functions and molecular mechanisms in RCC have not been studied...
September 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Hsiang-Ju Chen, Rui-Lan Huang, Phui-Ly Liew, Po-Hsuan Su, Lin-Yu Chen, Yu-Chun Weng, Cheng-Chang Chang, Yu-Chi Wang, Michael Wing-Yan Chan, Hung-Cheng Lai
Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy. Prevailing evidences suggest that drug resistance and recurrence of ovarian HGSC are caused by the presence of cancer stem cells. Therefore, targeting cancer stems is appealing, however, all attempts to date, have failed. To circumvent this limit, we analyzed differential transcriptomes at early differentiation of ovarian HGSC stem cells and identified the developmental transcription factor GATA3 as highly expressed in stem, compared to progenitor cells...
July 14, 2018: International Journal of Cancer. Journal International du Cancer
Xingrao Ke, Hollis Johnson, Xigang Jing, Teresa Michalkiewicz, Yi-Wen Huang, Robert H Lane, Girija G Konduri
Decreased expression of endothelial nitric oxide synthase (eNOS), a key mediator of perinatal transition, characterizes persistent pulmonary hypertension of the newborn (PPHN) in neonates and a fetal lamb model; the mechanisms are unclear. We investigated whether increased DNA CpG methylation at the eNOS promoter in estrogen response elements (EREs) and altered histone code together contribute to decreased eNOS expression in PPHN. We isolated pulmonary artery endothelial cells (PAEC) from fetal lambs with PPHN induced by prenatal ductus arteriosus constriction from 128-136 days gestation or gestation matched twin controls...
July 13, 2018: Physiological Genomics
Yuchen Chen, Xinran Liu, Yangkai Li, Chuntao Quan, Ling Zheng, Kun Huang
Lung cancer is one of the most common malignancies. In spite of the progress made in past decades, further studies to improve current therapy for lung cancer are required. Dynamically controlled by methyltransferases and demethylases, methylation of lysine and arginine residues on histone proteins regulates chromatin organization and thereby gene transcription. Aberrant alterations of histone methylation have been demonstrated to be associated with the progress of multiple cancers including lung cancer. Inhibitors of methyltransferases and demethylases have exhibited anti-tumor activities in lung cancer, and multiple lead candidates are under clinical trials...
2018: Computational and Structural Biotechnology Journal
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