How Substrate Specificity Is Imposed on a Histone Demethylase—Lessons from KDM2A
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Investigation of Histone Lysine-Specific Demethylase 5D
FULL LENGTH Iranian Biomedical Journal 20(2): 117-121 April 2016 Investigation of Histone Lysine-Specific Demethylase 5D (KDM5D) Isoform Expression in Prostate Cancer Cell Lines: a System Approach Zohreh Jangravi1, 2, Mohammad Najafi1,3 and Mohammd Shabani*1 1Dept. of Biochemistry, Iran University of Medical Sciences, Tehran, Iran; 2Dept. of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; 3Dept. of Biochemistry, Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran Received 2 September 2014; revised 3 December 2014; accepted 7 December 2014 ABSTRACT Background: It is now well-demonstrated that histone demethylases play an important role in developmental controls, cell-fate decisions, and a variety of diseases such as cancer. Lysine-specific demethylase 5D (KDM5D) is a male-specific histone demethylase that specifically demethylates di- and tri-methyl H3K4 at the start site of active gene. In this light, the aim of this study was to investigate isoform/transcript-specific expression profiles of KDM5D in three prostate cancer cell lines, Du-145, LNCaP, and PC3. Methods: Real-time PCR analysis was performed to determine the expression levels of different KDM5D transcripts in the prostate cell lines. A gene regulatory network was established to analyze the gene expression profile. Results: Significantly different expression levels of both isoforms were found among the three cell lines. Interestingly, isoform I was expressed in three cell lines while isoform III did only in DU-145. The expression levels of both isoforms were higher in DU-145 when compared to other cell lines (P<0.0001). -
High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer
Journal of Clinical Medicine Article High KDM1A Expression Associated with Decreased CD8+T Cells Reduces the Breast Cancer Survival Rate in Patients with Breast Cancer Hyung Suk Kim 1 , Byoung Kwan Son 2 , Mi Jung Kwon 3, Dong-Hoon Kim 4,* and Kyueng-Whan Min 5,* 1 Department of Surgery, Division of Breast Surgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Korea; [email protected] 2 Department of Internal Medicine, Eulji Hospital, Eulji University School of Medicine, Seoul 03181, Korea; [email protected] 3 Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068, Korea; [email protected] 4 Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Korea 5 Department of Pathology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Korea * Correspondence: [email protected] (D.-H.K.); [email protected] (K.-W.M.); Tel.: +82-2-2001-2392 (D.-H.K.); +82-31-560-2346 (K.-W.M.); Fax: +82-2-2001-2398 (D.-H.K.); Fax: +82-2-31-560-2402 (K.-W.M.) Abstract: Background: Lysine-specific demethylase 1A (KDM1A) plays an important role in epige- netic regulation in malignant tumors and promotes cancer invasion and metastasis by blocking the immune response and suppressing cancer surveillance activities. The aim of this study was to analyze Citation: Kim, H.S.; Son, B.K.; Kwon, survival, genetic interaction networks and anticancer immune responses in breast cancer patients M.J.; Kim, D.-H.; Min, K.-W. High with high KDM1A expression and to explore candidate target drugs. -
Lanosterol 14Α-Demethylase (CYP51)
463 Lanosterol 14-demethylase (CYP51), NADPH–cytochrome P450 reductase and squalene synthase in spermatogenesis: late spermatids of the rat express proteins needed to synthesize follicular fluid meiosis activating sterol G Majdicˇ, M Parvinen1, A Bellamine2, H J Harwood Jr3, WWKu3, M R Waterman2 and D Rozman4 Veterinary Faculty, Clinic of Reproduction, Cesta v Mestni log 47a, 1000 Ljubljana, Slovenia 1Institute of Biomedicine, Department of Anatomy, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland 2Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232–0146, USA 3Pfizer Central Research, Department of Metabolic Diseases, Box No. 0438, Eastern Point Road, Groton, Connecticut 06340, USA 4Institute of Biochemistry, Medical Center for Molecular Biology, Medical Faculty University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia (Requests for offprints should be addressed to D Rozman; Email: [email protected]) (G Majdicˇ is now at Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75235–8857, USA) Abstract Lanosterol 14-demethylase (CYP51) is a cytochrome detected in step 3–19 spermatids, with large amounts in P450 enzyme involved primarily in cholesterol biosynthe- the cytoplasm/residual bodies of step 19 spermatids, where sis. CYP51 in the presence of NADPH–cytochrome P450 P450 reductase was also observed. Squalene synthase was reductase converts lanosterol to follicular fluid meiosis immunodetected in step 2–15 spermatids of the rat, activating sterol (FF-MAS), an intermediate of cholesterol indicating that squalene synthase and CYP51 proteins are biosynthesis which accumulates in gonads and has an not equally expressed in same stages of spermatogenesis. additional function as oocyte meiosis-activating substance. -
Interplay Between Epigenetics and Metabolism in Oncogenesis: Mechanisms and Therapeutic Approaches
OPEN Oncogene (2017) 36, 3359–3374 www.nature.com/onc REVIEW Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches CC Wong1, Y Qian2,3 and J Yu1 Epigenetic and metabolic alterations in cancer cells are highly intertwined. Oncogene-driven metabolic rewiring modifies the epigenetic landscape via modulating the activities of DNA and histone modification enzymes at the metabolite level. Conversely, epigenetic mechanisms regulate the expression of metabolic genes, thereby altering the metabolome. Epigenetic-metabolomic interplay has a critical role in tumourigenesis by coordinately sustaining cell proliferation, metastasis and pluripotency. Understanding the link between epigenetics and metabolism could unravel novel molecular targets, whose intervention may lead to improvements in cancer treatment. In this review, we summarized the recent discoveries linking epigenetics and metabolism and their underlying roles in tumorigenesis; and highlighted the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these abnormalities in cancer. Oncogene (2017) 36, 3359–3374; doi:10.1038/onc.2016.485; published online 16 January 2017 INTRODUCTION metabolic genes have also been identified as driver genes It has been appreciated since the early days of cancer research mutated in some cancers, such as isocitrate dehydrogenase 1 16 17 that the metabolic profiles of tumor cells differ significantly from and 2 (IDH1/2) in gliomas and acute myeloid leukemia (AML), 18 normal cells. Cancer cells have high metabolic demands and they succinate dehydrogenase (SDH) in paragangliomas and fuma- utilize nutrients with an altered metabolic program to support rate hydratase (FH) in hereditary leiomyomatosis and renal cell 19 their high proliferative rates and adapt to the hostile tumor cancer (HLRCC). -
Mutant IDH, (R)-2-Hydroxyglutarate, and Cancer
Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer Julie-Aurore Losman1 and William G. Kaelin Jr.1,2,3 1Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA; 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA Mutations in metabolic enzymes, including isocitrate whether altered cellular metabolism is a cause of cancer dehydrogenase 1 (IDH1) and IDH2, in cancer strongly or merely an adaptive response of cancer cells in the face implicate altered metabolism in tumorigenesis. IDH1 of accelerated cell proliferation is still a topic of some and IDH2 catalyze the interconversion of isocitrate and debate. 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate The recent identification of cancer-associated muta- and an essential cofactor for many enzymes, including tions in three metabolic enzymes suggests that altered JmjC domain-containing histone demethylases, TET cellular metabolism can indeed be a cause of some 5-methylcytosine hydroxylases, and EglN prolyl-4-hydrox- cancers (Pollard et al. 2003; King et al. 2006; Raimundo ylases. Cancer-associated IDH mutations alter the enzymes et al. 2011). Two of these enzymes, fumarate hydratase such that they reduce 2OG to the structurally similar (FH) and succinate dehydrogenase (SDH), are bone fide metabolite (R)-2-hydroxyglutarate [(R)-2HG]. Here we tumor suppressors, and loss-of-function mutations in FH review what is known about the molecular mechanisms and SDH have been identified in various cancers, in- of transformation by mutant IDH and discuss their im- cluding renal cell carcinomas and paragangliomas. -
Neuro-Oncology Advances 1 1(1), 1–14, 2019 | Doi:10.1093/Noajnl/Vdz042 | Advance Access Date 5 November 2019
applyparastyle "fig//caption/p[1]" parastyle "FigCapt" applyparastyle "fig" parastyle "Figure" Neuro-Oncology Advances 1 1(1), 1–14, 2019 | doi:10.1093/noajnl/vdz042 | Advance Access date 5 November 2019 PELP1 promotes glioblastoma progression by enhancing Wnt/β-catenin signaling Gangadhara R. Sareddy, Uday P. Pratap, Suryavathi Viswanadhapalli, Prabhakar Pitta Venkata, Binoj C. Nair, Samaya Rajeshwari Krishnan, Siyuan Zheng, Andrea R. Gilbert, Andrew J. Brenner, Darrell W. Brann, and Ratna K. Vadlamudi Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas (G.R.S., U.P.P., S.V., P.P.V., B.C.N., S.R.K., R.K.V.); Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas (S.Z.); Department of Pathology and Laboratory Medicine, University of Texas Health San Antonio, San Antonio, Texas (A.R.G.); Hematology & Oncology, University of Texas Health San Antonio, San Antonio, Texas (A.J.B.); Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas (G.R.S., S.Z., A.J.B., R.K.V.); Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia (D.W.B.) Correspondence Author: Ratna K. Vadlamudi, Department of Obstetrics and Gynecology, 7703 Floyd Curl Drive, University of Texas Health San Antonio, San Antonio, TX 78229 ([email protected]). Abstract Background: Glioblastoma (GBM) is a deadly neoplasm of the central nervous system. The molecular mechanisms and players that contribute to GBM development is incompletely understood. Methods: The expression of PELP1 in different grades of glioma and normal brain tissues was analyzed using immunohistochemistry on a tumor tissue array. -
Combinatorial Genetic Control of Rpd3s Through Histone H3K4 and H3K36 Methylation
bioRxiv preprint doi: https://doi.org/10.1101/376046; this version posted July 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Combinatorial Genetic Control of Rpd3S through histone H3K4 and H3K36 Methylation 2 in Budding Yeast 3 4 Kwan Yin Lee*, Mathieu Ranger*, and Marc D. Meneghini* 5 *Department of Molecular Genetics, University of Toronto, ON, M5S 1A8, Canada 6 Running title: Rpd3S control by H3K4me and H3K36me 7 Keywords: Rpd3S; histone methylation; SET1; JHD2; RPH1; SET2 8 Corresponding author mailing addresses: 9 Marc Meneghini 10 Dept. of Molecular Genetics University of Toronto 11 MaRS2 1532 12 661 University Avenue 13 Toronto, ON M5G 1M1 14 Office: 416-978-7578 15 Fax: 416-978-6885 16 email: [email protected] 17 18 19 1 bioRxiv preprint doi: https://doi.org/10.1101/376046; this version posted July 24, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Abstract 2 Much of euchromatin regulation occurs through reversible methylation of histone H3 3 lysine-4 and lysine-36 (H3K4me and H3K36me). Using the budding yeast Saccharomyces 4 cerevisiae, we previously found that levels of H3K4me modulated temperature sensitive alleles 5 of the transcriptional elongation complex Spt6-Spn1 through an unknown H3K4me effector 6 pathway. Here we identify the Rpd3S histone deacetylase complex as the H3K4me effector 7 underlying these Spt6-Spn1 genetic interactions. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
Sterol Homeostasis Requires Regulated Degradation of Squalene
RESEARCH ARTICLE elife.elifesciences.org Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4 Ombretta Foresti1,2, Annamaria Ruggiano1,2, Hans K Hannibal-Bach3, Christer S Ejsing3, Pedro Carvalho1,2* 1Cell and Developmental Biology Programme, Center for Genomic Regulation (CRG), Barcelona, Spain; 2Universitat Pompeu Fabra, Barcelona, Spain; 3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark Abstract Sterol homeostasis is essential for the function of cellular membranes and requires feedback inhibition of HMGR, a rate-limiting enzyme of the mevalonate pathway. As HMGR acts at the beginning of the pathway, its regulation affects the synthesis of sterols and of other essential mevalonate-derived metabolites, such as ubiquinone or dolichol. Here, we describe a novel, evolutionarily conserved feedback system operating at a sterol-specific step of the mevalonate pathway. This involves the sterol-dependent degradation of squalene monooxygenase mediated by the yeast Doa10 or mammalian Teb4, a ubiquitin ligase implicated in a branch of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. Since the other branch of ERAD is required for HMGR regulation, our results reveal a fundamental role for ERAD in sterol homeostasis, with the two branches of this pathway acting together to control sterol biosynthesis at different levels and thereby allowing independent regulation of multiple products of the mevalonate pathway. DOI: 10.7554/eLife.00953.001 *For correspondence: pedro. [email protected] Introduction Sterols, such as cholesterol in animals or ergosterol in yeast, are essential components of cellular Competing interests: The authors membranes and their concentration to a large extent determines many of the membrane properties, declare that no competing interests exist. -
Recognition of Cancer Mutations in Histone H3K36 by Epigenetic Writers and Readers Brianna J
EPIGENETICS https://doi.org/10.1080/15592294.2018.1503491 REVIEW Recognition of cancer mutations in histone H3K36 by epigenetic writers and readers Brianna J. Kleina, Krzysztof Krajewski b, Susana Restrepoa, Peter W. Lewis c, Brian D. Strahlb, and Tatiana G. Kutateladzea aDepartment of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA; bDepartment of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC, USA; cWisconsin Institute for Discovery, University of Wisconsin, Madison, WI, USA ABSTRACT ARTICLE HISTORY Histone posttranslational modifications control the organization and function of chromatin. In Received 30 May 2018 particular, methylation of lysine 36 in histone H3 (H3K36me) has been shown to mediate gene Revised 1 July 2018 transcription, DNA repair, cell cycle regulation, and pre-mRNA splicing. Notably, mutations at or Accepted 12 July 2018 near this residue have been causally linked to the development of several human cancers. These KEYWORDS observations have helped to illuminate the role of histones themselves in disease and to clarify Histone; H3K36M; cancer; the mechanisms by which they acquire oncogenic properties. This perspective focuses on recent PTM; methylation advances in discovery and characterization of histone H3 mutations that impact H3K36 methyla- tion. We also highlight findings that the common cancer-related substitution of H3K36 to methionine (H3K36M) disturbs functions of not only H3K36me-writing enzymes but also H3K36me-specific readers. The latter case suggests that the oncogenic effects could also be linked to the inability of readers to engage H3K36M. Introduction from yeast to humans and has been shown to have a variety of functions that range from the control Histone proteins are main components of the of gene transcription and DNA repair, to cell cycle nucleosome, the fundamental building block of regulation and nutrient stress response [8]. -
Automethylation of PRC2 Promotes H3K27 Methylation and Is Impaired in H3K27M Pediatric Glioma
Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma Chul-Hwan Lee,1,2,7 Jia-Ray Yu,1,2,7 Jeffrey Granat,1,2,7 Ricardo Saldaña-Meyer,1,2 Joshua Andrade,3 Gary LeRoy,1,2 Ying Jin,4 Peder Lund,5 James M. Stafford,1,2,6 Benjamin A. Garcia,5 Beatrix Ueberheide,3 and Danny Reinberg1,2 1Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA; 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA; 3Proteomics Laboratory, New York University School of Medicine, New York, New York 10016, USA; 4Shared Bioinformatics Core, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 5Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/ EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring inde- pendently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. -
X Chromosome Dosage of Histone Demethylase KDM5C Determines Sex Differences in Adiposity
X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity Jenny C. Link, … , Arthur P. Arnold, Karen Reue J Clin Invest. 2020. https://doi.org/10.1172/JCI140223. Research Article Genetics Metabolism Graphical abstract Find the latest version: https://jci.me/140223/pdf The Journal of Clinical Investigation RESEARCH ARTICLE X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity Jenny C. Link,1 Carrie B. Wiese,2 Xuqi Chen,3 Rozeta Avetisyan,2 Emilio Ronquillo,2 Feiyang Ma,4 Xiuqing Guo,5 Jie Yao,5 Matthew Allison,6 Yii-Der Ida Chen,5 Jerome I. Rotter,5 Julia S. El -Sayed Moustafa,7 Kerrin S. Small,7 Shigeki Iwase,8 Matteo Pellegrini,4 Laurent Vergnes,2 Arthur P. Arnold,3 and Karen Reue1,2 1Molecular Biology Institute, 2Human Genetics, David Geffen School of Medicine, 3Integrative Biology and Physiology, and 4Molecular, Cellular and Developmental Biology, UCLA, Los Angeles, California, USA. 5Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA. 6Division of Preventive Medicine, School of Medicine, UCSD, San Diego, California, USA. 7Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom. 8Human Genetics, Medical School, University of Michigan, Ann Arbor, Michigan, USA. Males and females differ in body composition and fat distribution. Using a mouse model that segregates gonadal sex (ovaries and testes) from chromosomal sex (XX and XY), we showed that XX chromosome complement in combination with a high-fat diet led to enhanced weight gain in the presence of male or female gonads.