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

Abstract

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.

Novel Methylselenoesters Induce Programed Cell Death via Entosis in Pancreatic Cancer Cells

“…Cell adhesion is gaining more attention due to its implication in cancer metastasis and progression, in addition to drug resistance. Importantly, these results are in accordance with recent investigations revealing that MSA targeted adhesion molecules in a leukemic cancer cell line, whereas inorganic selenite affected other gene sets, indicating an interesting type-dependent effect of Se compounds [ 34 ]. To further confirm the compound-induced adhesion disturbance, levels of different adhesion molecules were screened 24 h after treatment.…”

Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels

“…This might partly explain the survival of immune cells upon treatment with selenite. MSA has however been reported in several studies to act via redox modulatory effects that do not mainly cause oxidative stress to the cells ( 28 ). In line with these previous studies, MSA did not trigger any Nrf2 response, indicating that immune cell resistance to MSA is achieved by a different molecular mechanism, again illustrating the distinct effect encompassed by each separate selenium metabolite ( 29 ).…”

“…We recently demonstrated that MSA affect a large set of genes involved in the loss of attachment of cells to the extracellular matrix. Among the many genes identified, several of the matrix metalloproteineases (MMPs) were found to be significantly upregulated in response to MSA ( 28 ). Methylselenol, the active metabolite of MSA, was also identified by Zeng and co-workers to activate MMP-2 and MMP-9 ( 30 ).…”

Methylseleninic Acid Suppresses Breast Cancer Growth via the JAK2/STAT3 Pathway

“…As an organic Se, MSA has few side effects, has excellent anticancer effects, and is easily absorbed compared to inorganic Se. 17,32 For example, MSA can reduce cell number in a dose-dependent manner. The inhibitory effect was equivalent to a 10-fold greater concentration of methyl selenocysteine acid, and the reaction was more pronounced and faster.…”