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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2021, Vol. 15 Issue (3) : 383-403    https://doi.org/10.1007/s11684-020-0818-1
REVIEW
Proteins moonlighting in tumor metabolism and epigenetics
Lei Lv1(), Qunying Lei2,3,4()
1. MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
2. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai 200032, China
3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
4. State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
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Abstract

Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signalmoonlighting proteinmetabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

Keywords moonlighting function      tumor metabolism      epigenetics     
Corresponding Author(s): Lei Lv,Qunying Lei   
Just Accepted Date: 20 November 2020   Online First Date: 22 December 2020    Issue Date: 18 June 2021
 Cite this article:   
Lei Lv,Qunying Lei. Proteins moonlighting in tumor metabolism and epigenetics[J]. Front. Med., 2021, 15(3): 383-403.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0818-1
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I3/383
Fig.1  The canonical and moonlighting functions of KRAS. The canonical (left panel) and non-canonical (right panel) functions of KRAS are summarized. Abbreviations: EGFR, epidermal growth factor receptor; GTP, guanosine triphosphate; GDP, guanosine diphosphate; PI3K, phosphatidylinositol 3-kinase; HK1, hexokinase 1.
Fig.2  The canonical and moonlighting functions of p53. The canonical and non-canonical functions of p53 are summarized. Abbreviations: G6P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; Bax, Bcl-2 associated X protein; Ub, ubiquitin.
Fig.3  The canonical and moonlighting functions of STAT3. The canonical and non-canonical functions of STAT3 are summarized. Abbreviations: STAT3, signal transducers and activators of transcription 3; JAK, Janus kinase.
Fig.4  The canonical and moonlighting functions of ALDO. The canonical and non-canonical functions of ALDO are summarized. Abbreviations: F6P, fructose-6-phosphate; FBP, fructose 1,6-bisphosphate; DHAP, dihydroxyacetone-3-phosopate; G3P, glyceraldehyde-3-phosphate; ER, endoplasmic reticulum; ALDO, aldolase; LKB1, liver kinase B1; AMPK, AMP-activated protein kinase.
Fig.5  The canonical and moonlighting functions of GAPDH. The canonical and non-canonical functions of GAPDH are summarized. Abbreviations: G6P, glucose-6-phosphate; 1,3-BPG, 1,3-bisphosphoglycerate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDAC2, histone deacetylase 2; SIRT1, sirtuin 1; SNO, S-nitrosylation; SSG, S-glutathionylation.
Fig.6  The canonical and moonlighting functions of PGK1. The canonical and non-canonical functions of PGK1 are summarized. Abbreviations: 1,3-BPG, 1,3-bisphosphoglycerate; 3-PG, 3-phosphoglycerate (3-PG); ADP, adenosine diphosphate; ATP, adenosine triphosphate; PGK1, phosphoglycerate kinase 1; SIRT7, sirtuin 1; PDK1, pyruvate dehydrogenase kinase 1; PDH, pyruvate dehydrogenase; OXPHOS, oxidative phosphorylation; O-GlcNAc, O-GlcNAcylation.
Fig.7  The canonical and moonlighting functions of PKM2. The canonical and non-canonical functions of PKM2 are summarized. Abbreviations: PEP, phosphoenolpyruvate; PKM2, pyruvate kinase M2; ERK2, extracellular signal-regulated kinase 2; HSC70, heat shock cognate 71 kDa protein; H3, histone H3; STAT3, signal transducers and activators of transcription 3; HIF-1a, hypoxia-inducible factor-1a.
Fig.8  The canonical and moonlighting functions of FBP1/2. The canonical and non-canonical functions of FBP1/2 are summarized. Abbreviations: F-6-P, fructose-6-phosphate; F-1,6-P, fructose-1,6-bisphosphate; FBP1/2, fructose-1,6-bisphosphatase 1/2; HIF, hypoxia-inducible factor; VEGF, vascular endothelial growth factor; GLUT1, glucose transporter 1; LDHA, lactate dehydrogenase A; TFAM, transcription factor A, mitochondrial.
Fig.9  The canonical and moonlighting functions of GDH. The canonical and non-canonical functions of GDH are summarized. Abbreviations: ROS, reactive oxygen species; GPx1, glutathione peroxidase 1; Gln, glutamine; Glu, glutamate; a-KG, a-ketoglutarate; GLS, glutaminase; GDH, glutamate dehydrogenase; AMPK, AMP-activated protein kinase; CamKK2, calcium/calmodulin dependent protein kinase kinase 2; NF-kB, nuclear factor kB; GLUT1, glucose transporter 1.
Fig.10  The canonical and moonlighting functions of LDHA. The canonical and non-canonical functions of LDHA are summarized. Abbreviations: G6P, glucose-6-phosphate; LDHA, lactate dehydrogenase A; CMA, chaperone-mediated autophagy; ROS, reactive oxygen species; a-KG, a-ketoglutarate; a-KB, a-ketobutyrate; L-2-HG, L-2-hydroxyglutarate; HIF-1a, hypoxia-inducible factor-1a; O2, oxygen; OH, hydroxylation; VHL, von Hippel-Lindau.
Fig.11  Metabolic enzymes moonlighting in regulation of epigenetics. The metabolic enzymes regulating epigenetics are summarized. Mutations in IDH, SDH, and FH accumulate 2-HG, succinate, and fumarate, respectively, thereby suppressing DNA and histone demethylation. The a-KB and Ac-CoA produced by LDHA and ACLY, respectively, promote histone H3K79 tri-methylation and acetylation. LDHA and MDH can also convert a-KG to L-2-HG at acidic pH. Abbreviations: G6P, glucose-6-phosphate; LDHA, lactate dehydrogenase A; a-KG, a-ketoglutarate; a-KB, a-ketobutyrate; L-2-HG, L-2-hydroxyglutarate; HIF-1a, hypoxia-inducible factor-1a; O2, oxygen; OH, hydroxylation; VHL, von Hippel-Lindau; ACLY, ATP-citrate lyase; MDH, malate dehydrogenase; IDH, isocitrate dehydrogenase; SDH, succinate dehydrogenase; FH, fumarate hydratase; O-GlcNAc, O-GlcNAcylation; ATF2, activating transcription factor 2; ROS, reactive oxygen species; Me, methylation; H3K79me3, H3K79 tri-methylation; Ac, acetylation.
Metabolic process Enzyme Canonical function Moonlight function in tumor metabolism and epigenetics
Location Function Location Function
Glycolysis ALDO Cytoplasm Converts fructose-1,6-biphosphate to dihydroxyacetone-3-phosopate and glyceraldehyde-3-phosphate ER surface Senses glucose availability through FBP binding and activates AMPK signaling under low glucose status [14,54]
GAPDH Cytoplasm Converts glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate and generates NADH Nucleus S122 phosphorylation by AMPK promotes nuclear translocation, activates SIRT1, and promotes autophagy and cells survival under glucose starvation [63]
Binds to OCA-S and increases histone H2B transcription, thereby affecting cell metabolism [64]
Cell membrane Forms a complex with transferrin and involved in iron metabolism [65]
PGK1 Cytoplasm Converts 1,3-bisphosphoglycerate to 3-phosphoglycerate and produces ATP Mitochondria Inactivates pyruvate dehydrogenase as a protein kinase, blocks pyruvate utilization and ROS production, and increases lactate production, thereby promoting the Warburg effect [69]
T255 O-GlcNAcylation promotes mitochondria localization, inhibits the activity of pyruvate dehydrogenase, and reduces oxidative phosphorylation [68]
Cytoplasm Phosphorylates Beclin1 at S30 and triggers autophagy under glutamine deprivation and hypoxia [71,72]
Nucleus Functions as a transcription factor, drives cell metastasis via repression of E-cadherin expression and metabolic reprogramming [73]
PKM2 Cytoplasm Converts phosphoenolpyruvate to pyruvate and produces ATP Nucleus Phosphorylates histone H3, upregulates c-Myc target genes, such as GLUT1 and LDHA, to promote the Warburg effect [82,84,85]
Phosphorylates STAT3 at Y705, promotes its transcriptional activity, and activates MEK5 expression to promote cell proliferation and tumor growth [86,87]
Functions as a co-transcription factor of HIF-1a and activates downstream target gene expression to reprogram tumor metabolism [8992]
LDHA Cytoplasm Converts pyruvate to lactate Nucleus Converts a-ketobutyrate to a-hydroxybutyrate, which promotes histone H3K79 tri-methylation and activates antioxidant gene expression and Wnt signaling pathway to maintain cellular redox balance and cervical cancer cell proliferation [130,131]
Cytoplasm Gains new activity to convert a-KG to L-2-hydroxyglutarate (L-2-HG) at acidic pH, thereby stabilizing HIF-1a [132]
Gluconeogenesis FBP1/2 Cytoplasm Converts fructose-1,6-bisphosphate to fructose-6-phosphate Nucleus FBP1 binds to HIF and decreases the expressions of its target genes, such as VEGF, GLUT1, and LDHA, to suppress tumor metabolism [104]
FBP1 binds to Notch1 and facilitates its degradation, thereby reducing the expressions of Notch1 target genes and inhibits breast tumorigenesis [105]
FBP2 binds to and suppresses c-Myc-mediated TFAM expression, which in turn represses mitochondrial biogenesis and respiration [15]
PCK1 Cytoplasm Converts oxaloacetate and GTP to phosphoenolpyruvate and CO2 ER AKT-mediated PCK1 S190 phosphorylation functions as a protein kinase to phosphorylate INSIG1, leading to the activation of SREBP proteins and the expression of genes required for lipogenesis [16]
TCA cycle IDH1 Cytoplasm Converts isocitrate to a-KG and produce NADPH (wild-type)
Converts a-KG to 2-hydroxyglutarate (2HG) (mutant)
Cytoplasm 2-HG accumulates in tumor cells, leading to the dysregulation of histone and DNA demethylation to block cell differentiation and promotes tumorigenesis, thereby activating mTORC1/2 signaling in the absence of EGFR/NF1/PTEN mutation [144,145]
IDH2 Mitochondria Mitochondria
SDH Mitochondria Converts succinate to fumarate (wild type)
Accumulates succinate (mutant)
Nucleus Accumulated succinate competitively inhibits the a-KG-dependent dioxygenases, including histone demethylases and TET family of 5mC hydroxylases [151]
FH Mitochondria Converts fumarate to L-malate (wild-type)
Accumulates fumarate (mutant)
Nucleus Accumulated fumarate competitively inhibits the a-KG dependent dioxygenases, including histone demethylases and TET family of 5mC hydroxylases [151]
Inhibits KDM2B-mediated histone H3 K36 demethylation and promotes DNA repair and cell survival [13,152]
O-GlcNAcylation of FH blocks AMPK-mediated phosphorylation; FH fails to form the FH-ATF2 complex and loses its transcriptional regulatory activity; tumor is maintained growth under glucose deficiency [153]
MDH1 Cytoplasm Converts malate to oxaloacetate Cytoplasm Gains new activity to convert a-KG to L-2-hydroxyglutarate (L-2-HG) at acidic pH, thereby stabilizing HIF-1a [132]
MDH2 Mitochondria Mitochondria
Glutaminolysis GLS1 Mitochondria Converts glutamine to glutamate Mitochondria Senses glutamine availability and initiates mitochondria fusion to help the cells to overcome energy crisis under low glutamine status [112]
GDH Mitochondria Converts glutamate to a-ketoglutarate and ammonia Mitochondria Manipulates the intracellular level of fumarate, which activates glutathione peroxidase 1 to scavenge reactive oxygen species, thereby maintaining redox homeostasis [116]
In LK1-B deficient lung cancer, a-KG produced by GDH1 activates CamKK2-AMPK signaling, resulting in energy production [119]
Under low glucose stimulation, a-KG produced by GDH1 directly activates NF-kB signaling, upregulates GLUT1 expression, and increases glucose uptake [120,121]
Fructose metabolism KHK-A Cytoplasm Converts fructose to fructose-1-phosphate Cytoplasm Phosphorylates and activates PRPS1, thereby promoting de novo nucleic acid synthesis and HCC tumorigenesis through pentose phosphate pathway [125]
KHK-A S80 phosphorylation phosphorylates p62 and prevents its ubiquitylation, thereby promoting gene expression via Nrf2 activation to reduce reactive oxygen species [126]
Others ACLY Cytoplasm Converts citrate to acetyl-CoA Nucleus Under growth factor stimulation and cell differentiation, ACLY-generated acetyl-CoA promotes histone acetylation and gene expression [155,156]
Tab.1  Summa ry of metabolic enzymes moonlighting in tumor metabolism and epigenetics
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