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

• Published in: International journal of oncology Vol. 42; no. 5; pp. 1822 - 1832
• Main Authors: POGRIBNY, IGOR P, TRYNDYAK, VOLODYMYR P, POGRIBNA, MARTA, SHPYLEVA, SVITLANA, SURRATT, GORDON, COSTA, GONÇALO GAMBOA DA, BELAND, FREDERICK A
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.05.2013; Spandidos Publications UK Ltd
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Cell cycle; Chromatin Assembly and Disassembly - genetics; Cisplatin - pharmacology; Deoxyribonucleic acid; DNA; DNA methylation; Down-Regulation; Epigenesis, Genetic; Epigenetics; Female; Gene Expression Regulation, Neoplastic - drug effects; histone modifications; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones - genetics; Histones - metabolism; Humans; Immunoglobulins; Iron - metabolism; Iron Chelating Agents - pharmacology; Kinases; LSD; Lysergic acid diethylamide; MCF-7 Cells; Metabolism; Protein expression; Proteins; Up-Regulation
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2013.1855

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, G1-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.