Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

Andrew G. Cox, Allison Tsomides, Andrew J. Kim, Diane Saunders, Katie L. Hwang, Kimberley J. Evason, Jerry Heidel, Kristin K. Brown, Min Yuan, Evan C. Lien, Byung Cheon Lee, Sahar Nissim, Bryan Dickinson, Sagar Chhangawala, Christopher J. Chang, John M. Asara, Yariv Houvras, Vadim N. Gladyshev, Wolfram Goessling

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.

Original languageEnglish
Pages (from-to)E5562-E5571
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number38
DOIs
Publication statusPublished - 2016 Sep 20

Keywords

  • Endoderm development
  • Liver cancer
  • p53
  • Selenium
  • Selenoproteins

ASJC Scopus subject areas

  • General

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    Cox, A. G., Tsomides, A., Kim, A. J., Saunders, D., Hwang, K. L., Evason, K. J., Heidel, J., Brown, K. K., Yuan, M., Lien, E. C., Lee, B. C., Nissim, S., Dickinson, B., Chhangawala, S., Chang, C. J., Asara, J. M., Houvras, Y., Gladyshev, V. N., & Goessling, W. (2016). Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 113(38), E5562-E5571. https://doi.org/10.1073/pnas.1600204113