title: 5-aza-2'-deoxycytidine activates iron uptake and heme biosynthesis by increasing c-Myc nuclear localization and binding to the E-boxes of transferrin receptor 1 (TfR1) and ferrochelatase (Fech) genes.
abstract: The hypomethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) and its derivatives have been successfully used for the treatment of myelodysplastic syndromes, and they frequently improve the anemia that usually accompanies these disorders. However, the molecular mechanisms underlying this action remain poorly understood. In this study, we used two erythroid models, murine erythroid leukemia cells and erythroid burst-forming unit-derived erythroblasts, to show that 5-aza-CdR induced erythroid differentiation and increased the expression of transferrin receptor 1 (TfR1) and ferrochelatase (Fech), thereby increasing iron uptake and heme biosynthesis. We have identified new regulatory E-boxes that lie outside of CpG islands in the TfR1 and Fech promoters, and the methylation status of these sites can be altered by 5-aza-CdR treatment. This in turn altered the binding of the transcription factor c-Myc to these promoter elements. Furthermore, 5-aza-CdR promoted the nuclear translocation of c-Myc and its binding to Max to form functional complexes. The coordinated actions of 5-aza-CdR on the methylation status of the target genes and in stimulating the nuclear translocation of c-Myc provide new molecular insights into the regulation of E-boxes and explain, at least in part, the increased erythroid response to 5-aza-CdR treatment.
authors: Chinese Academy of Sciences Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, 11 Zhongguancun Beiyitiao, Beijing 100190, China.
authors: Bo
authors: B
authors: Ning
authors: Gang
authors: G
authors: Liu
authors: Yuanyuan
authors: Y
authors: Liu
authors: Xiufen
authors: X
authors: Su
authors: Gregory J
authors: GJ
authors: Anderson
authors: Xin
authors: X
authors: Zheng
authors: Yanzhong
authors: Y
authors: Chang
authors: Mingzhou
authors: M
authors: Guo
authors: Yuanfang
authors: Y
authors: Liu
authors: Yuliang
authors: Y
authors: Zhao
authors: Guangjun
authors: G
authors: Nie
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D018899:CpG Islands / Q000502:physiology; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D041905:Erythroid Cells; D005294:Ferrochelatase / Q000378:metabolism*; D006418:Heme / Q000096:biosynthesis*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004791:Enzyme Inhibitors; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; C068422:Max protein, mouse; D006418:Heme; D000077209:Decitabine; D007501:Iron; D005294:Ferrochelatase; D001374:Azacitidine