Regulation of iron homeostasis by the p53-ISCU pathway

Sci Rep. 2015 Nov 12;5:16497. doi: 10.1038/srep16497.

Abstract

Accumulation of iron in tissues increases the risk of cancer, but iron regulatory mechanisms in cancer tissues are largely unknown. Here, we report that p53 regulates iron metabolism through the transcriptional regulation of ISCU (iron-sulfur cluster assembly enzyme), which encodes a scaffold protein that plays a critical role in Fe-S cluster biogenesis. p53 activation induced ISCU expression through binding to an intronic p53-binding site. Knockdown of ISCU enhanced the binding of iron regulatory protein 1 (IRP1), a cytosolic Fe-S protein, to an iron-responsive element in the 5' UTR of ferritin heavy polypeptide 1 (FTH1) mRNA and subsequently reduced the translation of FTH1, a major iron storage protein. In addition, in response to DNA damage, p53 induced FTH1 and suppressed transferrin receptor, which regulates iron entry into cells. HCT116 p53(+/+) cells were resistant to iron accumulation, but HCT116 p53(-/-) cells accumulated intracellular iron after DNA damage. Moreover, excess dietary iron caused significant elevation of serum iron levels in p53(-/-) mice. ISCU expression was decreased in the majority of human liver cancer tissues, and its reduced expression was significantly associated with p53 mutation. Our finding revealed a novel role of the p53-ISCU pathway in the maintenance of iron homeostasis in hepatocellular carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • DNA Damage
  • Ferritins / genetics
  • Ferritins / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • Homeostasis*
  • Humans
  • Intracellular Space / metabolism
  • Iron / metabolism*
  • Iron Regulatory Protein 1 / genetics
  • Iron Regulatory Protein 1 / metabolism
  • Iron-Sulfur Proteins / genetics
  • Iron-Sulfur Proteins / metabolism*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Oxidoreductases
  • Protein Binding
  • RNA Isoforms
  • Signal Transduction*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • ISCU protein, human
  • Iron-Sulfur Proteins
  • RNA Isoforms
  • Tumor Suppressor Protein p53
  • Ferritins
  • Iron
  • FTH1 protein, human
  • Oxidoreductases
  • Iron Regulatory Protein 1