Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia: A genome wide epigenetic analysis

Autor: Julian Walfridsson, Sören Lehmann, Anni Martikainen, Prajakta Khalkar, Hani Abdulkadir Ali, Mohsen Karimi Arzenani, Johanna Ungerstedt, Aristi P. Fernandes, Nuria Díaz Argelich, Paula Codó
Rok vydání: 2017
Předmět:
0301 basic medicine
Adult
Male
Histone H3 Lysine 4
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology)
Molecular Biology
Microbiology
Biochemistry or Biopharmacy)
Antineoplastic Agents
Selenious Acid
Biochemistry
Epigenesis
Genetic
03 medical and health sciences
Histone H3
Selenium
0302 clinical medicine
AML
Physiology (medical)
Cell Line
Tumor
Organoselenium Compounds
ChIP sequencing
Cell Adhesion
Humans
Epigenetics
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi)
molekylärbiologi
mikrobiologi
biokemi eller biofarmaci)
Aged
Aged
80 and over
biology
Chemistry
Histone marks
Middle Aged
ChIP-sequencing
Cell biology
030104 developmental biology
Histone
Acetylation
Leukemia
Myeloid
030220 oncology & carcinogenesis
Anticancer agents
biology.protein
H3K4me3
Female
Chromatin immunoprecipitation
Genome-Wide Association Study
Zdroj: Free radical biologymedicine. 117
ISSN: 1873-4596
Popis: Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line K562, on active (histone H3 lysine 9 acetylation, H3K9ac and histone H3 lysine 4 tri-methylation, H3K4me3) and repressive (histone H3 lysine 9 tri-methylation, H3K9me3) histone marks by Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). Both selenite and MSA had major effects on histone marks but the effects of MSA were more pronounced. Gene ontology analysis revealed that selenite affected genes involved in response to oxygen and hypoxia, whereas MSA affected distinct gene sets associated with cell adhesion and glucocorticoid receptors, also apparent by global gene expression analysis using RNA sequencing. The correlation to adhesion was functionally confirmed by a significantly weakened ability of MSA treated cells to attach to fibronectin and linked to decreased expression of integrin beta 1. A striking loss of cellular adhesion was also confirmed in primary patient AML cells. Recent strategies to enhance the cytotoxicity of chemotherapeutic drugs by disrupting the interaction between leukemic and stromal cells in the bone marrow are of increasing interest; and organic selenium compounds like MSA might be promising candidates. In conclusion, these results provide new insight on the mechanism of action of selenium compounds, and will be of value for the understanding, usage, and development of new selenium compounds as anticancer agents.
Databáze: OpenAIRE
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