Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Epigenetic Regulation in Cancer
2.1. DNA Methylation
2.2. Histone Marks
2.3. Chromatin Remodeling
3. Metabolic Dysregulation as a Driver of Cell Fate in Stem Cells and Cancer
3.1. Mitochondrial Metabolism in the Regulation of Cell Differentiation in Embryonic Stem Cells
3.2. Mitochondrial Metabolism in the Regulation of Cell Differentiation in Cancer Cells
3.3. Mitochondrial Transporters in the Epigenetic Regulation of Cell Differentiation
4. The Role of Hypoxia in Cancer Cell Differentiation
- (1)
- HIF is an α/β heterodimer that binds the hypoxia response elements (HREs) on the promoters of target genes, activating the hypoxic response. Whereas the β subunit is constitutively expressed, HIF-1α and HIF-2α are regulated post-translationally by an O2-dependent mechanism through hydroxylation of proline residues by prolyl hydroxylases (PHDs) and subsequent ubiquitination by pVHL [118,119]. The PHD enzymes are dioxygenases that require for their activity oxygen, as well as iron and αKG [120]. Therefore, HIF-1α/HIF-2α are constitutively degraded during normoxia, whereas during hypoxia they escape ubiquitination and proteasomal degradation and heterodimerize with HIF-1β to regulate transcription of downstream genes [121]. HIF target genes are involved in the regulation of cell proliferation, angiogenic signalling and altered metabolism [122]. The impact of HIFs on cancer stem cells is mostly attributed to the HIF-dependent activation of stemness factors. Hypoxia signalling can induce HIF-dependent expression of known pluripotent factors, such as KLF4, MYC, OCT4, SOX2, and NANOG, which have an important role in the dedifferentiation process under hypoxic conditions, inducing cancer stemness and repressing cancer cell differentiation [123]. It has been reported that cancer stem-like cells can be induced through de-differentiation under hypoxic conditions in glioma, hepatoma and lung cancer, providing new evidence about tumor development and chemoradiotherapy resistance [124].
- (2)
- Reduced availability of oxygen for the mitochondrial respiratory chain is expected to slow down the oxidation of NADH in the mitochondria, leading to feedback inhibition of the TCA cycle. Hypoxia has been shown to stimulate stemness of breast cancer cells by the production of reactive oxygen species, and this effect is mediated by attenuation of the TCA cycle and accumulation of fumarate [125]. Although the epigenetic consequences of these alterations have not been investigated in detail, they are likely to play a role in cell de-differentiation induced by hypoxia. Prolonged hypoxia can cause reduced activity of nuclear pyruvate dehydrogenase, resulting in reduced nuclear availability of acetyl-CoA and reduced histone acetylation [126].
- (3)
- An increasing number of studies have focused on the involvement of hypoxia in regulating multiple components of the epigenetic machinery, including DNA methylation, histone modification, non-coding RNAs (ncRNAs) and chromatin remodelling, affecting the expression of specific genes involved in cancer progression, dedifferentiation, and drug resistance [127,128]. Hypoxia interferes with the activity of oxygen-dependent dioxygenases, including the TET 5-methyl-cytosine dioxygenases and Jumonji-C (JMJC) histone demethylases [129]. As a consequence, hypoxia induces increased trimethylation marks on H3K4 and H3K36 in HeLa cells and in a human fibroblast line, and on H3K9 in several cell lines, including colon carcinoma and epithelial human breast cancer cell lines. These events are driven by the inactivation of the JMJC-containing enzymes, such as lysine demethylase 4A (KDM4A) and 5A (KDM5A). The lack of demethylase activity in hypoxic conditions leads to transcriptional repression of target genes and a phenotype of increased tumor aggressiveness, invasion, migration, and proliferation [130,131]. In addition, hypoxia is able to induce specific changes in the chromatin state associated with EMT. Wu et al. reported that under hypoxia, HDAC3 interacts with hypoxia-induced WDR5, recruits the HMT complex to increase the methylation marks on H3K4, and activates the transcription of mesenchymal genes [132]. Interestingly, the activity of lactate dehydrogenase A, under hypoxic conditions, is able to produce the oncometabolite L-2-hydroxyglutarate, independently of IDH. This event promotes the inhibition of KDM4C and enhanced H3K9 methylation, thus altering the expression of genes involved in cellular differentiation [133,134]. Thienpont et al. have also observed that increased promoter methylation is associated with reduced activity of TET enzymes, which decreases 5-hydroxymethyl-cytosine at gene promoters and enhancers, supporting the hypothesis that hypoxia inhibits TET-mediated DNA demethylation in tumors [135].
5. Therapeutic Implications
6. Concluding Remarks
Funding
Conflicts of Interest
Abbreviations
5mC | 5-methyl-cytosine |
AGC | aspartate-glutamate carrier |
AML | acute myeloid leukemia |
ATP | adenosine triphosphate |
CGI | CpG island |
CIC | citrate carrier |
DNA | deoxyribonucleic acid |
DNMT | DNA methyl-transferase |
DNMTi | DNA metyl-transferase inhibitors |
GlcNAc | N-acetylglucosamine |
GOT1/2 | glutamic-oxaloacetic transaminase |
H3K27ac | acetylated histone 3 lysine 27 |
H3K27me | methylated histone 3 lysine 27 |
H3K4me | methylated histone 3 lysine 4 |
H3K9me | methylated histone 3 lysine 9 |
HAT | histone acetyl-transferase |
HDAC | histone deacetylase |
HDACi | histone deacetylase inhibitors |
HDM | histone demethylase |
HIF | hypoxia inducible factors |
HMT | histone methyl transferase |
HMTi | histone methyl-transferase inhibitors |
IDH1-3 | isocitrate dehydrogenase |
IGF | insulin-like growth factor |
JHDM | Jumonji-domain containing histone demethylases |
cMDH | cytoplasmic malate dehydrogenase |
mMDH | mitochondrial malate dehydrogenase |
MDS | myelodysplastic syndromes |
MLL | mixed-lineage leukemia |
MPC | mitochondrial pyruvate carrier |
mtDNA | mitochondrial DNA |
NAD+ | oxidized nicotinamide adenine dinucleotide |
NADH | reduced nicotinamide adenine dinucleotide |
NAMPT | nicotinamide phosphoribosyl-transferase |
OGC | αKG (oxoglutarate)-glutamate carrier |
PHD | prolyl hydroxylase |
PHGDH | phosphoglycerate dehydrogenase |
RNA | ribonucleic acid |
TCA | tricarboxylic acid |
TET | ten-eleven translocation |
αKG | alpha-ketoglutarate |
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Saggese, P.; Sellitto, A.; Martinez, C.A.; Giurato, G.; Nassa, G.; Rizzo, F.; Tarallo, R.; Scafoglio, C. Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer. Cancers 2020, 12, 3788. https://doi.org/10.3390/cancers12123788
Saggese P, Sellitto A, Martinez CA, Giurato G, Nassa G, Rizzo F, Tarallo R, Scafoglio C. Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer. Cancers. 2020; 12(12):3788. https://doi.org/10.3390/cancers12123788
Chicago/Turabian StyleSaggese, Pasquale, Assunta Sellitto, Cesar A. Martinez, Giorgio Giurato, Giovanni Nassa, Francesca Rizzo, Roberta Tarallo, and Claudio Scafoglio. 2020. "Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer" Cancers 12, no. 12: 3788. https://doi.org/10.3390/cancers12123788