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
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 signal−moonlighting protein−metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.
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 [89–92]
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]
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