Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Abstract

Abstract. Iron plays a vital role in the normal functioning of cells via the regulation of essential cellular metabolic reactions, including several DNA and histone-modifying proteins. The metabolic status of iron and the regulation of epige netic mechanisms are well-balanced and tightly controlled in normal cells; however, in cancer cells these processes are profoundly disturbed. Cancer-related abnormalities in iron metabolism have been corrected through the use of iron-chelating agents, which cause an inhibition of DNA synthesis, G 1 -S phase arrest, an inhibition of epithelial-to-mesenchymal transition, and the activation of apoptosis. In the present study, we show that, in addition to these well-studied molecular mechanisms, the treatment of wild-type TP53 MCF-7 and mutant TP53 MDA-MB-231 human breast cancer cells with desferrioxamine (DFO), a model iron chelator, causes significant epigenetic alterations at the global and gene-specific levels. Specifically, DFO treatment decreased the protein levels of the histone H3 lysine 9 demethylase, Jumonji domain-containing protein 2A (JMJD2A), in the MCF-7 and MDA-MB-231 cells and down-regulated the levels of the histone H3 lysine 4 demethylase, lysine-specific demethylase 1 (LSD1), in the MDA-MB-231 cells. These changes were accompanied by alterations in corresponding metabolically sensitive histone marks. Additionally, we demonstrate that DFO treatment activates apoptotic programs in MCF-7 and MDA-MB-231 cancer cells and enhances their sensitivity to the chemotherapeutic agents, doxorubicin and cisplatin; however, the mechanisms underlying this activation differ. The induction of apoptosis in wild-type TP53 MCF-7 cells was p53-dependent, triggered mainly by the down-regulation of the JMJD2A histone demethylase, while in mutant TP53 MDA-MB-231 cells, the activation of the p53-independent apoptotic program was driven predominantly by the epigenetic up-regulation of p21. IntroductionA growing body of evidence indicates the existence of an intimate link between the metabolic status and epigenetic regulation of cells (1,2). This is exemplified by the fact that a variety of small molecules involved in intercellular metabolism, including adenosine triphosphate, S-adenosylmethionine, nicotinamide adenine dinucleotide, flavin adenine dinucleotide, folate, acetyl coenzyme A, α-ketoglutarate and iron, are essential for the proper maintenance of the cellular epigenome.Iron is an essential trace element for normal cellular function. In addition to its significance in controlling a variety of cellular processes, including proliferation, DNA synthesis and repair, and mitochondrial electron transport, which are essential for the accurate maintenance of normal cellular homeostasis, iron plays a key regulatory role in the functioning of DNA and histone-modifying proteins (3,4). Specifically, the Jumonji domain-containing histone demethylase (JHDM) family, which catalyzes the demethylation of tri-and dimethylated lysine 9 and lysine 36 residues in histone H3 (5,6) and ten-eleven tra...

Estrogen-Dependent Downregulation of Hepcidin Synthesis Induces Intracellular Iron Efflux in Cancer Cells In Vitro

“…However, further work is still needed to establish whether E2 treatment precipitates such effects on cancer cells. Should this prove to be the case, high dose E2 treatment could provide an alternative to the problematic employment of iron chelation as an anti-cancer therapy [29][30][31][32][33][34][35][36].…”

“…Furthermore, upregulated expression of CD71 is considered as a marker of poor prognosis in breast cancer patients [28]. Based on these and other relevant observations, iron chelation therapy has been proposed and tested in various forms of cancer [29][30][31][32][33] with mixed results regarding efficacy [34,35] and side effects [36]. One possible reason for the limited efficacy of iron chelation in cancer is that it mostly targets extracellular iron.…”

Cancer cells with irons in the fire

“…This study suggests that HFE expression could be a potential prognostic marker for tumor progression of HNSCC and that iron depletion may be a treatment option for this type of cancer. Similarly, studies on breast cancer cells indicated that the iron chelator deferoxamine (DFO) increased the sensitivity of these cells to chemotherapeutic agents [61]. …”

Inhibitory effect of iron withdrawal by chelation on the growth of human and murine mammary carcinoma and fibrosarcoma cells

“…Iron chelators as anti-cancer agents that may be able to synergize with other cancer therapies show potential to reduce tumor burden (Buss et al, 2003;Kalinowski and Richardson, 2005;Pogribny et al, 2013). However, iron chelators (deferasirox, deferoxamine, and deferiprone) that are currently available for clinical use have limitations such as adverse side effects, short biological half-life, and high cost (Neufeld, 2010).…”