Document Detail

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.
MedLine Citation:
PMID:  23483119     Owner:  NLM     Status:  Publisher    
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.
Igor P Pogribny; Volodymyr P Tryndyak; Marta Pogribna; Svitlana Shpyleva; Gordon Surratt; Gonçalo Gamboa da Costa; Frederick A Beland
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-3-12
Journal Detail:
Title:  International journal of oncology     Volume:  -     ISSN:  1791-2423     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-3-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA.
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