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Cited by 230Epigenetics and DNA MethylationChromatin Remodeling and CancerCancer, Hypoxia, and Metabolism

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The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism

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Chang, Soojeong, Yim, Sujin, Park, Hyunsung·2019·Experimental & Molecular Medicine
DOI 10.1038/s12276-019-0230-6PMC PMC6586683
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Abstract

Recent studies on mutations in cancer genomes have distinguished driver mutations from passenger mutations, which occur as byproducts of cancer development. The cancer genome atlas (TCGA) project identified 299 genes and 24 pathways/biological processes that drive tumor progression (Cell 173: 371-385 e318, 2018). Of the 299 driver genes, 12 genes are involved in histones, histone methylation, and demethylation. Among these 12 genes, those encoding the histone demethylases JARID1C/KDM5C and UTX/KDM6A were identified as cancer driver genes. Furthermore, gain-of-function mutations in genes encoding metabolic enzymes, such as isocitrate dehydrogenases (IDH)1/2, drive tumor progression by producing an oncometabolite, D-2-hydroxyglutarate (D-2HG), which is a competitive inhibitor of α-ketoglutarate, O2-dependent dioxygenases such as Jumonji domain-containing histone demethylases, and DNA demethylases. Studies on oncometabolites suggest that histone demethylases mediate metabolic changes in chromatin structure. We have reviewed the most recent findings regarding cancer-specific metabolic reprogramming and the tumor-suppressive roles of JARID1C/KDM5C and UTX/KDM6A. We have also discussed mutations in other isoforms such as the JARID1A, 1B, 1D of KDM5 subfamilies and the JMJD3/KDM6B of KDM6 subfamilies, which play opposing roles in tumor progression as oncogenes or tumor suppressors depending on the cancer cell type. Genes involved in the removal of methyl groups from histones associated with DNA can promote or suppress tumor growth depending on the metabolic status of the cancer cell. Hyunsung Park and colleagues at the University of Seoul, South Korea, review current knowledge of two genes encoding histone demethylases which have been identified by The Cancer Genome Atlas (TCGA) project as cancer driver genes. Because these demethylase enzymes rely on cellular metabolites to function, their effect is influenced by metabolic conditions in the tumor microenvironment such as low oxygen. The mechanisms through which changes in histone methylation affect the expression of genes involved in tumor progression remain unknown. Further understanding of how cancer metabolism affects the modification of histones will help guide the development of more effective cancer treatments.

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Fig. 1 Functional domains and substrates of O2- and α-KG-dependent histone demethylases. a Substrates for O2- and α-KG-dependent histone demethylases. JHDMs (JmjC domain-containing histone demethylases) remove methyl (CH3-) groups from methylated lysines. JHDMs require O2, α-ketoglutarate, Fe(II), and vitamin C (vit C) for their catalytic activities and release CO2, succinate, and Fe(III). b Schematic illustration of the protein domains of histone demethylases. The domain architecture from the UniProt or NCBI gene (KDM1A, B) information was transformed using https://prosite.expasy.org/mydomains/. The numbers written in each functional domain column indicate the number of amino acids. ARID AT-rich interacting domain, amino oxidase amine oxidase domain, C5HC2 C5HC2 zinc-finger domain, CW CW-type zinc-finger domain, CXXC CXXC zinc-finger domain, C6 C6 zinc-finger domain, JMJC Jumonji C domain, LRR Leu-rich repeat domain, PHD plant homeodomain, SWIRM Swi3p, Rsc8p, and Moira domain, TPR tetratricopeptide domain, TUDOR Tudor domain
Fig. 1 Functional domains and substrates of O2- and α-KG-dependent histone demethylases. a Substrates for O2- and α-KG-dependent histone demethylases. JHDMs (JmjC domain-containing histone demethylases) remove methyl (CH3-) groups from methylated lysines. JHDMs require O2, α-ketoglutarate, Fe(II), and vitamin C (vit C) for their catalytic activities and release CO2, succinate, and Fe(III). b Schematic illustration of the protein domains of histone demethylases. The domain architecture from the UniProt or NCBI gene (KDM1A, B) information was transformed using https://prosite.expasy.org/mydomains/. The numbers written in each functional domain column indicate the number of amino acids. ARID AT-rich interacting domain, amino oxidase amine oxidase domain, C5HC2 C5HC2 zinc-finger domain, CW CW-type zinc-finger domain, CXXC CXXC zinc-finger domain, C6 C6 zinc-finger domain, JMJC Jumonji C domain, LRR Leu-rich repeat domain, PHD plant homeodomain, SWIRM Swi3p, Rsc8p, and Moira domain, TPR tetratricopeptide domain, TUDOR Tudor domainCC BY · PubMed Central
Fig. 2 Schematic showing signal control vs. metabolic control. Metabolic control and signaling control interpret how the levels of O2, α-ketoglutarate (α-KG), and 2-hydroxyglutarate (2-HG) modulate gene expression by altering histone methylation. DNA-bound proteins (DBP) or DNA-bound long noncoding RNAs recruit histone demethylases (KDM), such as JARID and JMJD. In low oxygen or α-KG concentrations and a 2-HG high concentration, the activities of JARID or JMJD are suppressed at different loci for each cell, resulting in a high methylation level on the corresponding loci. Transcription factors (TF) such as hypoxia-inducible factor (HIF) are activated under low oxygen conditions or high 2-HG conditions. Activated TFs recruit histone methyltransferase (HMT), which forms a complex with KDM. In most cells, although KDM and HMT are recruited together, the histone methylation level was upregulated by HMT, as the KDM activity is suppressed under hypoxic or high 2-HG conditions. Dynamic histone modification can regulate transcription, replication, and DNA repair
Fig. 2 Schematic showing signal control vs. metabolic control. Metabolic control and signaling control interpret how the levels of O2, α-ketoglutarate (α-KG), and 2-hydroxyglutarate (2-HG) modulate gene expression by altering histone methylation. DNA-bound proteins (DBP) or DNA-bound long noncoding RNAs recruit histone demethylases (KDM), such as JARID and JMJD. In low oxygen or α-KG concentrations and a 2-HG high concentration, the activities of JARID or JMJD are suppressed at different loci for each cell, resulting in a high methylation level on the corresponding loci. Transcription factors (TF) such as hypoxia-inducible factor (HIF) are activated under low oxygen conditions or high 2-HG conditions. Activated TFs recruit histone methyltransferase (HMT), which forms a complex with KDM. In most cells, although KDM and HMT are recruited together, the histone methylation level was upregulated by HMT, as the KDM activity is suppressed under hypoxic or high 2-HG conditions. Dynamic histone modification can regulate transcription, replication, and DNA repairCC BY · PubMed Central
Fig. 3 Metabolic reactions that alter the effective α-KG concentration. Glucose and glutamine are transported inside cells using individual transporters (circles with arrows). Glucose is converted to pyruvate via glycolysis, which is then converted into acetyl CoA by PDH and used in the TCA cycle. Intermediates in the TCA cycle, from citrate to oxaloacetate, are converted by individual enzymes. IDH1 and IDH2 are localized in the cytosol and mitochondria, respectively. Both enzymes convert isocitrate to α-KG. Glutamine is converted to glutamate by GLS, which can be converted to α-KG by GDH or AT. α-KG is used as a substrate by α-KG-dependent dioxygenase together with oxygen and iron ions. The types of α-KG-dependent dioxygenases include enzymes that induce metabolic epigenetic changes in histones, DNA, and RNA, and enzymes that induce changes in signaling. As these enzymes are α-KG- and O2-dependent, they are inhibited via deprivation of these factors. Regarding α-KG, (i) mutated IDH1/2 and PHGDH produce D-2HG, and (ii) LDHA and MDH1/2, whose levels are increased under hypoxic conditions, produce L-2HG. Both types of 2-HG compete with α-KG to inhibit α-KG-dependent dioxygenases. Both D-2HG and L-2HG can be converted to α-KG by D2HGDH and L2HGDH, respectively. Under hypoxic conditions, the activity of α-KG-dependent dioxygenases is inhibited via the regulation of glucose and glutamine pathways as well as by the O2 concentration. Hypoxia increases glycolysis by upregulating glucose transporters and enzymes related to glycolysis. Hypoxia-inducible factor 1 alpha (HIF1α) activates PDK, an enzyme that inactivates PDH (which converts pyruvate to acetyl-CoA); therefore, hypoxia inhibits the entry of pyruvate into the TCA cycle. Glutamine uptake and GDH (the enzyme that converts glutamate to α-KG) are upregulated under hypoxic conditions. Glutamine is converted to α-KG to provide intermediates for the TCA cycle. Details are provided in the text and the enzymes are shown in green. AT aminotransferases, D2HGDH D-2HG dehydrogenase, FH fumarate hydratase, FTO fat mass and obesity-associated protein, GDH glutamate dehydrogenases, GLS glutaminase, IDH1/2 isocitrate dehydrogenases 1/2, JHDM JmjC domain-containing histone demethylases, L2HGDH L-2HG dehydrogenase, LDHA lactate dehydrogenase A, MDH 1/2 malate dehydrogenase 1/2, PDH pyruvate dehydrogenase, PDK1 pyruvate dehydrogenase kinase 1, PHGDH D-3-phosphoglycerate dehydrogenase, SDH succinate dehydrogenase, TET ten-eleven translocation, TCA tricarboxylic acid
Fig. 3 Metabolic reactions that alter the effective α-KG concentration. Glucose and glutamine are transported inside cells using individual transporters (circles with arrows). Glucose is converted to pyruvate via glycolysis, which is then converted into acetyl CoA by PDH and used in the TCA cycle. Intermediates in the TCA cycle, from citrate to oxaloacetate, are converted by individual enzymes. IDH1 and IDH2 are localized in the cytosol and mitochondria, respectively. Both enzymes convert isocitrate to α-KG. Glutamine is converted to glutamate by GLS, which can be converted to α-KG by GDH or AT. α-KG is used as a substrate by α-KG-dependent dioxygenase together with oxygen and iron ions. The types of α-KG-dependent dioxygenases include enzymes that induce metabolic epigenetic changes in histones, DNA, and RNA, and enzymes that induce changes in signaling. As these enzymes are α-KG- and O2-dependent, they are inhibited via deprivation of these factors. Regarding α-KG, (i) mutated IDH1/2 and PHGDH produce D-2HG, and (ii) LDHA and MDH1/2, whose levels are increased under hypoxic conditions, produce L-2HG. Both types of 2-HG compete with α-KG to inhibit α-KG-dependent dioxygenases. Both D-2HG and L-2HG can be converted to α-KG by D2HGDH and L2HGDH, respectively. Under hypoxic conditions, the activity of α-KG-dependent dioxygenases is inhibited via the regulation of glucose and glutamine pathways as well as by the O2 concentration. Hypoxia increases glycolysis by upregulating glucose transporters and enzymes related to glycolysis. Hypoxia-inducible factor 1 alpha (HIF1α) activates PDK, an enzyme that inactivates PDH (which converts pyruvate to acetyl-CoA); therefore, hypoxia inhibits the entry of pyruvate into the TCA cycle. Glutamine uptake and GDH (the enzyme that converts glutamate to α-KG) are upregulated under hypoxic conditions. Glutamine is converted to α-KG to provide intermediates for the TCA cycle. Details are provided in the text and the enzymes are shown in green. AT aminotransferases, D2HGDH D-2HG dehydrogenase, FH fumarate hydratase, FTO fat mass and obesity-associated protein, GDH glutamate dehydrogenases, GLS glutaminase, IDH1/2 isocitrate dehydrogenases 1/2, JHDM JmjC domain-containing histone demethylases, L2HGDH L-2HG dehydrogenase, LDHA lactate dehydrogenase A, MDH 1/2 malate dehydrogenase 1/2, PDH pyruvate dehydrogenase, PDK1 pyruvate dehydrogenase kinase 1, PHGDH D-3-phosphoglycerate dehydrogenase, SDH succinate dehydrogenase, TET ten-eleven translocation, TCA tricarboxylic acidCC BY · PubMed Central

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Metadata

Authors
Chang, S., Yim, S., & Park, H.
Affiliations
University of Seoul (KR)
Corresponding author
Park, Hyunsung
ORCID
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-06
Volume
51
Issue
6
Pages
1-17
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/s12276-019-0230-6
PMC
PMC6586683
OpenAlex
W2950853065
Cited by
228
References
147
Citations by year
2026: 8 · 2025: 31 · 2024: 41 · 2023: 37 · 2022: 32 · 2021: 50 · 2020: 24 · 2019: 4
FWCI
2.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Research Foundation of Korea (2016R1A2B4012840, 2018R1A4A1025985)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
histone demethylation, histone methylation, cancer driver genes, cancer metabolism, D-2-hydroxyglutarate, oncometabolites, tumor suppressor, JARID1A, JARID1B, chromatin
MeSH terms
Tumor Hypoxia, Nucleophosmin, Animals, Histones, Humans, Isocitrate Dehydrogenase, Neoplasms, Gene Expression Regulation, Neoplastic, Histone Demethylases

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