title: Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis.
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.
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Andrew G
authors: AG
authors: Cox
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Allison
authors: A
authors: Tsomides
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Andrew J
authors: AJ
authors: Kim
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Diane
authors: D
authors: Saunders
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Katie L
authors: KL
authors: Hwang
authors: University of Utah, Salt Lake City, UT 84112;
authors: Kimberley J
authors: KJ
authors: Evason
authors: Oregon State University, Corvallis, OR 97331;
authors: Jerry
authors: J
authors: Heidel
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors: Kristin K
authors: KK
authors: Brown
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors: Min
authors: M
authors: Yuan
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors: Evan C
authors: EC
authors: Lien
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Korea University, 02841 Seoul, Republic of Korea;
authors: Byung Cheon
authors: BC
authors: Lee
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Sahar
authors: S
authors: Nissim
authors: University of Chicago, Chicago, IL 60637;
authors: Bryan
authors: B
authors: Dickinson
authors: Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065;
authors: Sagar
authors: S
authors: Chhangawala
authors: Howard Hughes Medical Institute, Bethesda, MD 20815; University of California, Berkeley, CA 20815;
authors: Christopher J
authors: CJ
authors: Chang
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors: John M
authors: JM
authors: Asara
authors: Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065;
authors: Yariv
authors: Y
authors: Houvras
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors: Vadim N
authors: VN
authors: Gladyshev
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142; Harvard Stem Cell Institute, Cambridge, MA 02138; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 wgoessling@partners.org.
authors: Wolfram
authors: W
authors: Goessling
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D012643:Selenium / Q000378:metabolism; D051140:Selenoproteins / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D051140:Selenoproteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C519118:selenoprotein H, human; D012643:Selenium
keywords: endoderm development; liver cancer; p53; selenium; selenoproteins