Circadian clock in a mouse colon tumor regulates intracellular iron levels to promote tumor progression

Fumiyasu Okazaki, Naoya Matsunaga, Hiroyuki Okazaki, Hiroki Azuma, Kengo Hamamura, Akito Tsuruta, Yuya Tsurudome, Takashi Ogino, Yukinori Hara, Takuya Suzuki, Kenji Hyodo, Hiroshi Ishihara, Hiroshi Kikuchi, Hideto To, Hironori Aramaki, Satoru Koyanagi, Shigehiro Ohdo

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)


Iron is an important biological catalyst and is critical forDNA synthesis during cell proliferation. Cellular iron uptake is enhanced in tumor cells to support increased DNA synthesis. Circadian variations in DNA synthesis and proliferation have been identified in tumor cells, but their relationship with intracellular iron levels is unclear. In this study, we identified a 24-h rhythm in iron regulatory protein 2 (IRP2) levels in colon-26 tumors implanted in mice. Our findings suggest that IRP2 regulates the 24-h rhythm of transferrin receptor 1 (Tfr1) mRNA expression post-transcriptionally, by binding toRNAstem-loop structures known as iron-response elements.Wealso found that Irp2 mRNA transcription is promoted by circadian clock genes, including brain and muscle Arnt-like 1 (BMAL1) and the circadian locomotor output cycles kaput (CLOCK) heterodimer. Moreover, growth in colon-26(δ19) tumors expressing the clock-mutant protein (CLOCKδ19) was low compared with that in wild-type colon-26 tumor. The time-dependent variation of cellular iron levels, and the proliferation rate in wild-type colon-26 tumor was decreased by CLOCKδ19 expression. Our findings suggest that circadian organization contributes to tumor cell proliferation by regulating iron metabolism in the tumor.

Original languageEnglish
Pages (from-to)7017-7028
Number of pages12
JournalJournal of Biological Chemistry
Issue number13
Publication statusPublished - Mar 25 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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