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

Producción científica: Article › revisión exhaustiva

332 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	285-292
Número de páginas	8
Publicación	Cell Metabolism
Volumen	19
N.º	2
DOI	https://doi.org/10.1016/j.cmet.2013.11.022
Estado	Published - feb 4 2014

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
National Childhood Cancer Registry – National Cancer Institute	R01CA163581

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2013.11.022

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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. ",

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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.

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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.

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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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