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

doi:10.1073/pnas.1600204113

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^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

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 language	English (US)
Pages (from-to)	E5562-E5571
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	38
DOIs	https://doi.org/10.1073/pnas.1600204113
State	Published - Sep 20 2016

Funding

This work was supported by an Irwin Arias Postdoctoral Fellowship (to A.G.C.) and Liver Scholar Award (to A.G.C.) from the American Liver Foundation; Harvard Digestive Disease Center Pilot Feasibility Grant P30 DK034854 (to A.G.C.); and National Institutes of Health (NIH) Grants T32GM007753 (to K.L.H.), NCI 5K08CA172288 (to K.J.E.), R01 GM061603 (to V.N.G.), and R01 DK090311 and R24OD017870 (to W.G.). K.J.E. was a Robert Black Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-109-10). C.J.C. is an Investigator with the Howard Hughes Medical Institute and has received support from NIH Grant GM 79465. J.M.A. is partially supported by NIH Grants 5P01CA120964 and 5P30CA006516. W.G. is supported by the Claudia Adams Barr Program for Innovative Cancer Research and is a Pew Scholar in the Biomedical Sciences.

Keywords

Endoderm development
Liver cancer
Selenium
Selenoproteins
p53

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1600204113

Cite this

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

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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.",

keywords = "Endoderm development, Liver cancer, Selenium, Selenoproteins, p53",

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

year = "2016",

month = sep,

day = "20",

doi = "10.1073/pnas.1600204113",

language = "English (US)",

volume = "113",

pages = "E5562--E5571",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Cox, AG, Tsomides, A, Kim, AJ, Saunders, D, Hwang, KL, Evason, KJ, Heidel, J, Brown, KK, Yuan, M, Lien, EC, Lee, BC, Nissim, S, Dickinson, B, Chhangawala, S, Chang, CJ, Asara, JM, Houvras, Y, Gladyshev, VN & 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, vol. 113, no. 38, pp. E5562-E5571. https://doi.org/10.1073/pnas.1600204113

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis. / Cox, Andrew G.; Tsomides, Allison; Kim, Andrew J. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 38, 20.09.2016, p. E5562-E5571.

Research output: Contribution to journal › Article › peer-review

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T1 - Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

AU - Cox, Andrew G.

AU - Tsomides, Allison

AU - Kim, Andrew J.

AU - Saunders, Diane

AU - Hwang, Katie L.

AU - Evason, Kimberley J.

AU - Heidel, Jerry

AU - Brown, Kristin K.

AU - Yuan, Min

AU - Lien, Evan C.

AU - Lee, Byung Cheon

AU - Nissim, Sahar

AU - Dickinson, Bryan

AU - Chhangawala, Sagar

AU - Chang, Christopher J.

AU - Asara, John M.

AU - Houvras, Yariv

AU - Gladyshev, Vadim N.

AU - Goessling, Wolfram

PY - 2016/9/20

Y1 - 2016/9/20

N2 - 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.

AB - 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.

KW - Endoderm development

KW - Liver cancer

KW - Selenium

KW - Selenoproteins

KW - p53

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U2 - 10.1073/pnas.1600204113

DO - 10.1073/pnas.1600204113

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AN - SCOPUS:84988977423

SN - 0027-8424

VL - 113

SP - E5562-E5571

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 38

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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