Abstract
Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we call glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic payoff phase enzymes (PGK1, PGAM1, ENO1, and PKM2) along with lactate dehydrogenase A (LDHA). The gLINC metabolon enhances glycolytic flux, increases ATP production, and enables cell survival under serine deprivation. Furthermore, gLINC overexpression in cancer cells promotes xenograft growth in mice fed a diet deprived of serine, suggesting that cancer cells employ gLINC during metabolic reprogramming. We propose that gLINC makes a functional contribution to cancer cell adaptation and provide the first example of a lncRNA-facilitated metabolon.
Keywords:
c-Myc; glycoLINC; glycolytic complex; metabolon; serine starvation.
Copyright © 2021 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Proliferation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Female
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Glycolysis*
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HEK293 Cells
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HeLa Cells
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Hep G2 Cells
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Humans
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L-Lactate Dehydrogenase / genetics
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L-Lactate Dehydrogenase / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Nude
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Multienzyme Complexes
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Neoplasms / enzymology*
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Neoplasms / genetics
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Neoplasms / pathology
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Phosphoglycerate Kinase / genetics
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Phosphoglycerate Kinase / metabolism*
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Phosphoglycerate Mutase / genetics
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Phosphoglycerate Mutase / metabolism*
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Phosphopyruvate Hydratase / genetics
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Phosphopyruvate Hydratase / metabolism*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Long Noncoding / genetics
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RNA, Long Noncoding / metabolism*
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Serine / deficiency
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Thyroid Hormone-Binding Proteins
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Thyroid Hormones / genetics
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Thyroid Hormones / metabolism*
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Tumor Burden
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Biomarkers, Tumor
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Carrier Proteins
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DNA-Binding Proteins
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MYC protein, human
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Membrane Proteins
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Multienzyme Complexes
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Proto-Oncogene Proteins c-myc
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RNA, Long Noncoding
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Thyroid Hormones
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Tumor Suppressor Proteins
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Serine
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Adenosine Triphosphate
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L-Lactate Dehydrogenase
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LDHA protein, human
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PGK1 protein, human
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Phosphoglycerate Kinase
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ENO1 protein, human
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Phosphopyruvate Hydratase
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Phosphoglycerate Mutase
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phosphoglycerate mutase 1, human