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

• Published in: Free radical biology & medicine 2018-03, Vol.117, p.247-257
• Main Authors: Khalkar, Prajakta, Ali, Hani Abdulkadir, Codó, Paula, Argelich, Nuria Díaz, Martikainen, Anni, Arzenani, Mohsen Karimi, Lehmann, Sören, Walfridsson, Julian, Ungerstedt, Johanna, Fernandes, Aristi P.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; AML; Anticancer agents; Antineoplastic Agents - pharmacology; Cancer och onkologi; Cell Adhesion - drug effects; Cell Line, Tumor; ChIP sequencing; Epigenesis, Genetic - drug effects; Female; Genome-Wide Association Study; Histone marks; Humans; Klinisk medicin; Leukemia, Myeloid; Male; Medicin och hälsovetenskap; Medicinsk bioteknologi; Medicinsk bioteknologi (inriktn. mot cellbiologi (inkl. stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Organoselenium Compounds - pharmacology; Selenious Acid - pharmacology; Selenium
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.02.014

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. [Display omitted] •Genome wide epigenetic alterations caused by selenite and MSA were studied.•These compounds exert cytotoxic effects by affecting key histone modifications.•Selenite mainly affects pathways involving oxygen and hypoxia responses.•MSA mainly affects adhesion and migration pathways, causing cellular detachment.•MSA along with conventional therapy might overcome resistance phenotype in leukemia.