Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth

Ramon C. Sun; Nicholas C. Denko

doi:10.1016/j.cmet.2013.11.022

Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth

Ramon C. Sun, Nicholas C. Denko

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

295 Scopus citations

Abstract

Recent reports have identified a phenomenon by which hypoxia shifts glutamine metabolism from oxidation to reductive carboxylation. We now identify the mechanism by which HIF-1 activation results in a dramatic reduction in the activity of the key mitochondrial enzyme complex α ketoglutarate dehydrogenase (αKGDH). HIF-1 activation promotes SIAH2 targeted ubiquitination and proteolysis of the 48 kDa splice variant of the E1 subunit of the αKGDH complex (OGDH2). Knockdown of SIAH2 or mutation of the ubiquitinated lysine residue on OGDH2 (336KA) reverses the hypoxic drop in αKGDH activity, stimulates glutamine oxidation, and reduces glutamine-dependent lipid synthesis. 336KA OGDH2-expressing cells require exogenous lipids or citrate for growth in hypoxia in vitro and fail to grow as model tumors in immunodeficient mice. Reversal of hypoxic mitochondrial function may provide a target for the development of next-generation anticancer agents targeting tumor metabolism.

Original language	English
Pages (from-to)	285-292
Number of pages	8
Journal	Cell Metabolism
Volume	19
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2013.11.022
State	Published - Feb 4 2014

Bibliographical note

Funding Information:
This work was supported by the NCI (NCD). The authors would like to thank the proteomics core at OSU CCC. They would also like to thank Drs. Ioanna Papandreou, Amato Giaccia, Ze’ev Ronai, Naduparambil Jacob, Deliang Guo, and members of the N.C.D. lab for their helpful discussions.

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Access to Document

10.1016/j.cmet.2013.11.022

Cite this

@article{079d79cea18246489f22aa49631a0f84,

title = "Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth",

abstract = "Recent reports have identified a phenomenon by which hypoxia shifts glutamine metabolism from oxidation to reductive carboxylation. We now identify the mechanism by which HIF-1 activation results in a dramatic reduction in the activity of the key mitochondrial enzyme complex α ketoglutarate dehydrogenase (αKGDH). HIF-1 activation promotes SIAH2 targeted ubiquitination and proteolysis of the 48 kDa splice variant of the E1 subunit of the αKGDH complex (OGDH2). Knockdown of SIAH2 or mutation of the ubiquitinated lysine residue on OGDH2 (336KA) reverses the hypoxic drop in αKGDH activity, stimulates glutamine oxidation, and reduces glutamine-dependent lipid synthesis. 336KA OGDH2-expressing cells require exogenous lipids or citrate for growth in hypoxia in vitro and fail to grow as model tumors in immunodeficient mice. Reversal of hypoxic mitochondrial function may provide a target for the development of next-generation anticancer agents targeting tumor metabolism.",

author = "Sun, {Ramon C.} and Denko, {Nicholas C.}",

note = "Funding Information: This work was supported by the NCI (NCD). The authors would like to thank the proteomics core at OSU CCC. They would also like to thank Drs. Ioanna Papandreou, Amato Giaccia, Ze{\textquoteright}ev Ronai, Naduparambil Jacob, Deliang Guo, and members of the N.C.D. lab for their helpful discussions. ",

year = "2014",

month = feb,

day = "4",

doi = "10.1016/j.cmet.2013.11.022",

language = "English",

volume = "19",

pages = "285--292",

number = "2",

}

TY - JOUR

T1 - Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth

AU - Sun, Ramon C.

AU - Denko, Nicholas C.

N1 - Funding Information: This work was supported by the NCI (NCD). The authors would like to thank the proteomics core at OSU CCC. They would also like to thank Drs. Ioanna Papandreou, Amato Giaccia, Ze’ev Ronai, Naduparambil Jacob, Deliang Guo, and members of the N.C.D. lab for their helpful discussions.

PY - 2014/2/4

Y1 - 2014/2/4

N2 - Recent reports have identified a phenomenon by which hypoxia shifts glutamine metabolism from oxidation to reductive carboxylation. We now identify the mechanism by which HIF-1 activation results in a dramatic reduction in the activity of the key mitochondrial enzyme complex α ketoglutarate dehydrogenase (αKGDH). HIF-1 activation promotes SIAH2 targeted ubiquitination and proteolysis of the 48 kDa splice variant of the E1 subunit of the αKGDH complex (OGDH2). Knockdown of SIAH2 or mutation of the ubiquitinated lysine residue on OGDH2 (336KA) reverses the hypoxic drop in αKGDH activity, stimulates glutamine oxidation, and reduces glutamine-dependent lipid synthesis. 336KA OGDH2-expressing cells require exogenous lipids or citrate for growth in hypoxia in vitro and fail to grow as model tumors in immunodeficient mice. Reversal of hypoxic mitochondrial function may provide a target for the development of next-generation anticancer agents targeting tumor metabolism.

AB - Recent reports have identified a phenomenon by which hypoxia shifts glutamine metabolism from oxidation to reductive carboxylation. We now identify the mechanism by which HIF-1 activation results in a dramatic reduction in the activity of the key mitochondrial enzyme complex α ketoglutarate dehydrogenase (αKGDH). HIF-1 activation promotes SIAH2 targeted ubiquitination and proteolysis of the 48 kDa splice variant of the E1 subunit of the αKGDH complex (OGDH2). Knockdown of SIAH2 or mutation of the ubiquitinated lysine residue on OGDH2 (336KA) reverses the hypoxic drop in αKGDH activity, stimulates glutamine oxidation, and reduces glutamine-dependent lipid synthesis. 336KA OGDH2-expressing cells require exogenous lipids or citrate for growth in hypoxia in vitro and fail to grow as model tumors in immunodeficient mice. Reversal of hypoxic mitochondrial function may provide a target for the development of next-generation anticancer agents targeting tumor metabolism.

UR - http://www.scopus.com/inward/record.url?scp=84893465244&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893465244&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2013.11.022

DO - 10.1016/j.cmet.2013.11.022

M3 - Article

C2 - 24506869

AN - SCOPUS:84893465244

SN - 1550-4131

VL - 19

SP - 285

EP - 292

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth

Abstract

Bibliographical note

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this