title: Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization, stability, and function.
abstract: Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report that the tumor suppressor protein p53 is downregulated during iron excess. Strikingly, the iron polyporphyrin heme binds to p53 protein, interferes with p53-DNA interactions, and triggers both nuclear export and cytosolic degradation of p53. Moreover, in a tumorigenicity assay, iron deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of wild-type p53 signaling underlies the selective efficacy of iron deprivation. Our findings thus identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also help predict and improve outcomes in iron-deprivation-based chemotherapy.
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Zenan
authors.initials: Z
authors.lastname: Chang
authors.affiliation: University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Institute of Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: College of Chemistry and Materials, Anhui Normal University, Wuhu, Anhui 241000, China.
authors.forename: Zongliang
authors.initials: Z
authors.lastname: Xuan
authors.affiliation: University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Yalan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: College of Chemistry and Materials, Anhui Normal University, Wuhu, Anhui 241000, China.
authors.forename: Yongjia
authors.initials: Y
authors.lastname: Shang
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Xiangtao
authors.initials: X
authors.lastname: Kong
authors.affiliation: Institute of Genetics, Fudan University, Shanghai 200433, China.
authors.forename: Long
authors.initials: L
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Kangchen
authors.initials: K
authors.lastname: Ruan
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Hui
authors.affiliation: Institute of Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Xie
authors.affiliation: School of Public Health, Zhejiang University, Zhejiang 310027, China.
authors.forename: Fudi
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Cancer Research Center, Shanghai Xu-Hui Central Hospital, Shanghai Clinical Center, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: coryhu@sibs.ac.cn.
authors.forename: Ronggui
authors.initials: R
authors.lastname: Hu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D006418:Heme / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006418:Heme; D007501:Iron