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

Chang, Soojeong; Yim, Sujin; Park, Hyunsung

doi:10.1038/s12276-019-0230-6

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

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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Cancer cells in tumors with IDH1 or IDH2 mutations show oncogenic activity by converting glutamine-derived α-KG to 2-HG, which competitively inhibits α-KG-dependent histone and DNA modification enzymes.
“Cancer cells in tumors with IDH1 or IDH2 mutations show oncogenic activity by converting glutamine-derived α-KG to 2-hydroxyglutarate (2-HG), which competitively inhibits α-KG-dependent histone and DNA modification enzymes27.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [27]

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Transcription factor-dependent ‘anti-repressive’ mammalian enhancers exclude H3K27me3 from extended genomic domainsPreprint
Saxena, M., Roman, A. K. S., O’Neill, N. K., Sulahian, R., Jadhav, U., & Shivdasani, R. A. (2017) · Genes & Development · doi:10.1101/gad.308536.117 · Cited by 37 · see citing works
The Role of NF-κB and H3K27me3 Demethylase, Jmjd3, on the Anthrax Lethal Toxin Tolerance of RAW 264.7 Cells
Das, N. D., Jung, K. H., & Chai, Y. G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009913 · Cited by 32 · see citing works
Utx loss causes myeloid transformation
Zheng, L., Xu, L., Xu, Q., Yu, L., Zhao, D., Chen, P., Wang, W., Wang, Y., Han, G., & Chen, C. D. (2018) · Leukemia · doi:10.1038/s41375-018-0011-6 · Cited by 26 · see citing works
Amino acids in epidermal carcinogenesis in mice.
Roberts, E., & Caldwell, A. (1949) · PubMed · Cited by 20 · see citing works
Comprehensive molecular characterization of urothelial bladder carcinoma
Weinstein, J. N., Akbani, R., Broom, B. M., et al. (2014) · Nature · doi:10.1038/nature12965 · Cited by 10 · see citing works

Flagged first, then by citations

Sorted by citations

Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy
Yang, W., Qiu, Y., Stamatatos, O. T., Janowitz, T., & Lukey, M. J. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.04.003 · Cited by 300 · see citing works
Sunitinib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers
Jin, J., Xie, Y., Zhang, J.-S., Wang, J., Dai, S.-J., He, W., Li, S.-Y., Ashby, C. R., Chen, Z., & He, Q. (2023) · Drug Resistance Updates · doi:10.1016/j.drup.2023.100929 · Cited by 171 · see citing works
Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications
Shi, R., Liao, C., & Zhang, Q. H. (2021) · Cells · doi:10.3390/cells10030678 · Cited by 148 · see citing works
“2-HG can also affect the activity of oxygen-dependent enzymes such as JmjC histone demethylases and DNA demethylases [99].”
Background
Short-chain fatty acids in cancer pathogenesis
Feitelson, M. A., Arzumanyan, A. L., Medhat, A., & Spector, I. (2023) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10117-y · Cited by 149 · see citing works
Immunosuppressive Property of MSCs Mediated by Cell Surface Receptors
Liu, S., Liu, F., Zhou, Y. L., Jin, B., Sun, Q., & Guo, S. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01076 · Cited by 100 · see citing works
Glutamine Is Required for M1-like Polarization of Macrophages in Response to Mycobacterium tuberculosis Infection
Jiang, Q., Qiu, Y., Kurland, I. J., Drlica, K., Subbian, S., Tyagi, S., & Shi, L. (2022) · mBio · doi:10.1128/mbio.01274-22 · Cited by 98 · see citing works
Role of Metabolism in Bone Development and Homeostasis
Suzuki, A., Minamide, M., Iwaya, C., Ogata, K., & Iwata, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238992 · Cited by 90 · see citing works
“Mutations in IDH1 also accelerate the conversion of α-ketoglutarate to D-2-hydroxyglutarate and the accumulation of D-2-hydroxyglutarate, which is known as an oncometabolite competing withα-ketoglutarate in binding to histone and DNA demethylases, leading to chromatin hypermethylation [160,161].”
Background
Circulating RNAs in prostate cancer patients
Mugoni, V., Ciani, Y., Nardella, C., & Demichelis, F. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.10.011 · Cited by 89 · see citing works
KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1
Liu, L., Cui, J., Zhao, Y., Liu, X., Chen, L., Xia, Y., Wang, Y., Chen, S., Sun, S., Shi, B., et al. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01369-9 · Cited by 87 · see citing works
“KDM6A has also been shown to be involved in the establishment of the active histone marks H3K4 methylation and H3K27 acetylation in a demethylase activity-independent manner via recruitment of the COMPASS-like complex and histone acetyltransferase p300 [10, 33].”
Background
A noncoding single-nucleotide polymorphism at 8q24 drives IDH1 -mutant glioma formation
Yanchus, C., Drucker, K. L., Kollmeyer, T. M., Tsai, R., Winick‐Ng, W., Liang, M., Malik, A., Pawling, J., Lorenzo, S. B. D., Ali, A., et al. (2022) · Science · doi:10.1126/science.abj2890 · Cited by 73 · see citing works
Altered Gene-Regulatory Function of KDM5C by a Novel Mutation Associated With Autism and Intellectual Disability
Vallianatos, C. N., Farrehi, C., Friez, M. J., Burmeister, M., Keegan, C. E., & Iwase, S. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00104 · Cited by 71 · see citing works
The rapidly changing landscape in mature T‐cell lymphoma (MTCL) biology and management
Marchi, E., & O’Connor, O. A. (2019) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21589 · Cited by 66 · see citing works
Histone demethylases in the regulation of immunity and inflammation
Qu, L., Yin, T., Zhao, Y., Lv, W., Liu, Z., Chen, C., Liu, K., Shan, S., Zhou, R., Li, X., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01489-9 · Cited by 63 · see citing works
“Histones were the first proteins identified as lysine methylation substrates, while enzymes mediating methylation and demethylation were called histone methyltransferases (KMTs) and histone demethylases (KDMs) [7, 8].”
Background
Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity
Das, P., & Taube, J. H. (2020) · Cancers · doi:10.3390/cancers12102792 · Cited by 57 · see citing works
“Since 2-HG inhibits both the Jumanji-C domain containing histone lysine demethylases and the TET family of enzymes [293,294], both pathways for removing methylation may be impacted.”
Background
X- and Y-Linked Chromatin-Modifying Genes as Regulators of Sex-Specific Cancer Incidence and Prognosis
Tricarico, R., Nicolas, É., Hall, M. J., & Golemis, E. A. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-1741 · Cited by 60 · see citing works
Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance
Dratkiewicz, E., Simiczyjew, A., Mazurkiewicz, J., Ziętek, M., Matkowski, R., & Nowak, D. (2021) · Cells · doi:10.3390/cells10040862 · Cited by 61 · see citing works
Functions and Interactions of Mammalian KDM5 Demethylases
Pavlenko, E. A., Ruengeler, T., Engel, P., & Poepsel, S. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.906662 · Cited by 57 · see citing works
Zinc and its binding proteins: essential roles and therapeutic potential
Kiouri, D. P., Chasapis, C. T., Mavromoustakos, T., Spiliopoulou, C., & Stefanidou, M. E. (2024) · Archives of Toxicology · doi:10.1007/s00204-024-03891-3 · Cited by 56 · see citing works
KDM6 Demethylases and Their Roles in Human Cancers
Hua, C., Chen, J., Li, S., Zhou, J., Fu, J., Sun, W., & Wang, W. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.779918 · Cited by 56 · see citing works
“Glucose and glutamine respectively are transported into cells and both are converted to a-KG, which related to 2-hydroxyglutarate (2-HG) (10).”
BackgroundInfluential
Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies
Lv, M., Huang, Y., Chen, Y., & Ding, K. (2025) · Experimental Hematology and Oncology · doi:10.1186/s40164-025-00622-x · Cited by 50 · see citing works
“…modifications are involved in various tumor cell processes, including proliferation [4], invasion [5], metastasis [6], and metabolic reprogramming [7], etc. Metabolic alterations are hallmarks of cancer, including increased aerobic glycolysis, elevated glucose uptake, dysregulated glutamine…”
Significance of KDM6A mutation in bladder cancer immune escape
Chen, X., Lin, X., Pang, G., Deng, J., Xie, Q., & Zhang, Z. (2021) · BMC Cancer · doi:10.1186/s12885-021-08372-9 · Cited by 48 · see citing works
“Our present analysis of the somatic mutation landscape data of BC samples from the TCGA dataset (412 cases) and ICGC dataset (101 cases) confirmed that KDM6A was frequently mutated in both cohorts, in line with previous studies [6, 19].”
Result
Lactylproteome analysis indicates histone H4K12 lactylation as a novel biomarker in triple-negative breast cancer
Cui, Z., Li, Y., Lin, Y., Zheng, C., Luo, L., Hu, D., Chen, Y., Xiao, Z., & Sun, Y. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1328679 · Cited by 47 · see citing works
The role of histone post-translational modifications in cancer and cancer immunity: functions, mechanisms and therapeutic implications
Duan, X., Xing, Z., Qiao, L., Qin, S., Zhao, X., Gong, Y., & Li, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1495221 · Cited by 48 · see citing works
Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia
Frost, J., Frost, M. G., Batie, M., Jiang, H., & Rocha, S. (2021) · Cancers · doi:10.3390/cancers13020350 · Cited by 47 · see citing works
“2-OGDs can be inhibited by metabolites that are accumulated in tumours, including succinate, fumarate and D/L-2-hydroxyglutarate [318,319].”
Background
KIF11 Serves as an Independent Prognostic Factor and Therapeutic Target for Patients With Lung Adenocarcinoma
Li, Z., Yu, B., Qi, F., & Li, F. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.670218 · Cited by 42 · see citing works
“Advances in recent years, such as the identification of oncogenes and immunotherapy treatments, have provided valuable insight to guide the management of LUAD (6, 7).”
Background
A three layered histone epigenetics in breast cancer metastasis
Nandy, D., Rajam, S. M., & Dutta, D. (2020) · Cell & Bioscience · doi:10.1186/s13578-020-00415-1 · Cited by 40 · see citing works
High Risk-Human Papillomavirus in HNSCC: Present and Future Challenges for Epigenetic Therapies
Ghiani, L., & Chiocca, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073483 · Cited by 40 · see citing works
“Moreover, HPVmediated downregulation of KDM5C activates the expression of oncogenes such as EGFR and c-MET through the activation of cancer super-enhancers [31,90].”
BackgroundInfluential
The molecular code of kidney cancer: A path of discovery for gene mutation and precision therapy
Xie, D., Li, G., Zheng, Z., Zhang, X., Wang, S., Jiang, B., Li, X., Wang, X., & Wu, G. (2024) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2024.101335 · Cited by 38 · see citing works
Alterations of Chromatin Regulators in the Pathogenesis of Urinary Bladder Urothelial Carcinoma
Hoffmann, M. J., & Schulz, W. A. (2021) · Cancers · doi:10.3390/cancers13236040 · Cited by 37 · see citing works
Comprehensive Profiling of Genomic and Transcriptomic Differences between Risk Groups of Lung Adenocarcinoma and Lung Squamous Cell Carcinoma
Zengin, T., & Önal-Süzek, T. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11020154 · Cited by 33 · see citing works
“Additionally, EGFR [102], MGA [103], SMARCA4 [104], ATM [105], RBM10 [106] and KDM5C [107] which are lung cancer related genes are mutated only in LUAD but not in LUSC.”
BackgroundInfluential
Hypoxia in Lung Cancer Management: A Translational Approach
Ancel, J., Perotin, J., Dewolf, M., Launois, C., Mulette, P., Nawrocki‐Raby, B., Dalstein, V., Gilles, C., Deslée, G., Polette, M., et al. (2021) · Cancers · doi:10.3390/cancers13143421 · Cited by 32 · see citing works
Glutamate dehydrogenase 1-catalytic glutaminolysis feedback activates EGFR/PI3K/AKT pathway and reprograms glioblastoma metabolism
Yang, R., Zhang, G., Meng, Z., Wang, L., Li, Y., Li, H., Yan, S., Wei, X., Wang, S., & Cui, H. (2024) · Neuro-Oncology · doi:10.1093/neuonc/noae222 · Cited by 35 · see citing works
From the (Epi)Genome to Metabolism and Vice Versa; Examples from Hematologic Malignancy
Karagianni, P., Giannouli, S., & Voulgarelis, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126321 · Cited by 32 · see citing works
KDM5c Promotes Colon Cancer Cell Proliferation Through the FBXW7-c-Jun Regulatory Axis
Lin, H., Ma, N., Zhao, L., Yang, G., & Cao, B. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.535449 · Cited by 30 · see citing works
Advances in Chromodomain Helicase DNA-Binding (CHD) Proteins Regulating Stem Cell Differentiation and Human Diseases
Liu, C., Kang, N., Guo, Y., & Gong, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.710203 · Cited by 29 · see citing works
Comprehensive analyses of prognostic biomarkers and immune infiltrates among histone lysine demethylases (KDMs) in hepatocellular carcinoma
Qu, L.-H., Fang, Q., Yin, T., Yi, H.-M., Mei, G., Hong, Z.-Z., Qiu, X., Zhou, R., & Dong, H. (2022) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-022-03167-8 · Cited by 29 · see citing works
“However, KDM5C has been found to have a tumor-suppressive role in renal clear cell carcinoma, pancreatic cancer, and HPV-related cancers [62].”
Background
The Epigenetics of Glioma Stem Cells: A Brief Overview
Valor, L. M., & Hervás-Corpión, I. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.602378 · Cited by 28 · see citing works
“Additionally, mutations in arginine 132 of the tricarboxylic acid cycle component IDH1 (or in arginine 172 of IDH2), which are associated with longer survival, induce the overproduction of the 2-hydroxybutyrate metabolite that inhibits the a-ketoglutarate-dependent activity of epigenetic enzymes such as JumonjiC histo…”
Background
Catalysis by KDM6 Histone Demethylases – A Synergy between the Non‐Heme Iron(II) Center, Second Coordination Sphere, and Long‐Range Interactions
Rifayee, S. B. J. S., Chaturvedi, S. S., Warner, C., Wildey, J., White, W., Thompson, M. J., Schofield, C. J., & Christov, C. Z. (2023) · Chemistry - A European Journal · doi:10.1002/chem.202301305 · Cited by 27 · see citing works
Comprehensive review and updated analysis of DNA methylation in hepatocellular carcinoma: From basic research to clinical application
Su, L., Bu, J., Yu, J., Jin, M., Meng, G., & Zhu, X. (2024) · Clinical and Translational Medicine · doi:10.1002/ctm2.70066 · Cited by 26 · see citing works
“In addition, histone H4 methylation (H4 M) modification is also a key epigenetic modification and is involved in the development of HCC. 26,27 It also has different patterns under the heterogeneity of HCC. Yu et al. enrolled 2305 HCC samples and performed consensus clustering analysis, then they…”
Analysis in epithelial ovarian cancer identifies KANSL1 as a biomarker and target gene for immune response and HDAC inhibition
Fejzo, M. S., Chen, H., Anderson, L. A., McDermott, M. S. J., Karlan, B. Y., Konecny, G. E., & Slamon, D. J. (2020) · Gynecologic Oncology · doi:10.1016/j.ygyno.2020.11.008 · Cited by 26 · see citing works
Classifying Breast Cancer Molecular Subtypes by Using Deep Clustering Approach
Rohani, N., & Eslahchi, C. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.553587 · Cited by 26 · see citing works
“Studies on oncometabolite have shown that the KDM 5 C is involved in cancer-related metabolic reprogramming and the tumor suppression (Chang et al., 2019).”
Background
Critical roles and clinical perspectives of RNA methylation in cancer
Li, G., Yao, Q., Liu, P., Zhang, H., Liu, Y., Li, S., Shi, Y., Li, Z., & Zhu, W. (2024) · MedComm · doi:10.1002/mco2.559 · Cited by 27 · see citing works
“332,333 Moreover, the accumulation of certain mitochondrial metabolites in the TME has been found to contribute to cancer progression.”
Background
The Emerging Significance of Histone Lysine Demethylases as Prognostic Markers and Therapeutic Targets in Head and Neck Cancers
Dorna, D., & Paluszczak, J. (2022) · Cells · doi:10.3390/cells11061023 · Cited by 25 · see citing works
Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer
Chen, D., Cai, B., Zhu, Y., Ma, Y., Yu, X., Xiong, J., Shen, J., Tie, W., Zhang, Y., & Guo, F. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01665-3 · Cited by 24 · see citing works
“Previous research has shown that JMJD3 and UTX have oncogenic properties in various malignancies [39, 40].”
Background
Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema
Antunes, M. A., Braga, C. L., Oliveira, T. B., Kitoko, J. Z., de Castro, L. L., Xisto, D. G., Coelho, M., Rocha, N. N., Silva-Aguiar, R. P., Caruso‐Neves, C., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.661385 · Cited by 24 · see citing works
DNA Hydroxymethylation in Smoking-Associated Cancers
Nia, A. B., Caceres, A., & Tommasi, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052657 · Cited by 23 · see citing works
Energy metabolism as the hub of advanced non-small cell lung cancer management: a comprehensive view in the framework of predictive, preventive, and personalized medicine
Bajinka, O., Ouédraogo, S. Y., Golubnitschaja, O., Li, N., & Zhan, X. (2024) · The EPMA Journal · doi:10.1007/s13167-024-00357-5 · Cited by 24 · see citing works
Mechanism, Clinical Significance, and Treatment Strategy of Warburg Effect in Hepatocellular Carcinoma
Chen, H., Wu, Q., Peng, L., Cao, T., Deng, M.-L., Liu, Y.-W., Huang, J., Hu, Y., Fu, N., Zhou, K.-B., et al. (2021) · Journal of Nanomaterials · doi:10.1155/2021/5164100 · Cited by 22 · see citing works
“IDH mutation changes the active site of the enzyme and endows the enzyme with new catalytic activity, using α-ketoglutar-ate (α-KG) to produce high levels of R-2-hydrox-yglutarate (R-2-HG); the molecular structure of 2-HG and α-KG is very similar [52], and it is speculated that 2-HG may participate in OXPHOS by inhibi…”
Background
Development of JmjC-domain-containing histone demethylase (KDM2-7) inhibitors for cancer therapy
Zhang, L., Chen, Y., Li, Z., Lin, C., Zhang, T., & Wang, G. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103519 · Cited by 22 · see citing works
Downregulation of PSAT1 inhibits cell proliferation and migration in uterine corpus endometrial carcinoma
Wang, M., Yue, S., & Yang, Z. (2023) · Scientific Reports · doi:10.1038/s41598-023-31325-0 · Cited by 22 · see citing works
Hypoxia-Inducible Lysine Methyltransferases: G9a and GLP Hypoxic Regulation, Non-histone Substrate Modification, and Pathological Relevance
Chopra, A., Cho, W. C. S., Willmore, W. G., & Biggar, K. K. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.579636 · Cited by 22 · see citing works
“The catalytic activity of JmjC KDMs is also specifically tied to the individual affinities for molecular oxygen (Km;O2), in addition to other metabolic factors that are inherent to metabolism in the hypoxic environment (Chang et al., 2019).”
Background
Molecular and Metabolic Subtypes in Sporadic and Inherited Clear Cell Renal Cell Carcinoma
Czyzyk-Krzeska, M., Figueroa, J. A. L., Gulati, S., Cunningham, J. T., Meller, J., Shamsaei, B., Vemuri, B., & Plas, D. R. (2021) · Genes · doi:10.3390/genes12030388 · Cited by 22 · see citing works
“Other iron utilizing ketoglutarate-dependent dioxygenases include the enzyme-regulating epigenome, such as TET dioxygenases that remove the methyl group from pyrimidine bases in DNA [100], Jumonji domain containing histone lysine demethylases [101], and AlkB-type dioxygenases that are DNA repair enzymes performing oxi…”
Background
Epigenomic and Metabolomic Integration Reveals Dynamic Metabolic Regulation in Bladder Cancer
Loras, A., Segovia, C., & Ruiz-Cerdá, J. L. (2021) · Cancers · doi:10.3390/cancers13112719 · Cited by 21 · see citing works
Structures and nucleic acid-binding preferences of the eukaryotic ARID domain
Korn, S. M., & Schlundt, A. (2022) · Biological Chemistry · doi:10.1515/hsz-2021-0404 · Cited by 21 · see citing works
“While some members of the Arid family actively function as tumor suppressors (Bluemn et al. 2019; Chang et al. 2019; Luchini et al. 2015), overexpression of others provokes opposing effects in tumor growth [reviewed in (Lin et al. 2014)].”
Background
The role of lysine-specific demethylase 6A (KDM6A) in tumorigenesis and its therapeutic potentials in cancer therapy
Chen, L., Xu, X.-Y., Zhong, X.-D., Liu, Y., Zhu, M.-H., Tao, F., Li, C.-Y., She, Q. S., Yang, G.-J., & Chen, J. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106409 · Cited by 21 · see citing works
Cellular hierarchy framework based on single-cell/multi-patient sample sequencing reveals metabolic biomarker PYGL as a therapeutic target for HNSCC
Guan, J., Xu, X., Qiu, G., He, C., Lu, X., Wang, K., Liu, X., Li, Y., Ling, Z., Tang, X., et al. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02734-w · Cited by 21 · see citing works
“Recent studies on metabolic reprogramming in HNSCC have provided promising potential targets in the treatment of HNSCC [36–38], demonstrating that comprehensively research on metabolic heterogeneity and relevant metabolic mechanisms is significantly demanded.”
HIST1H1E heterozygous protein‐truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals
Burkardt, D. D., Zachariou, A., Loveday, C., Allen, C. L., Amor, D. J., Ardissone, A., Banka, S., Bourgois, A., Coubes, C., Cytrynbaum, C. S., et al. (2019) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61321 · Cited by 21 · see citing works
Myogenin controls via AKAP6 non-centrosomal microtubule-organizing center formation at the nuclear envelope
Becker, R., Vergarajauregui, S., Billing, F., Sharkova, M., Lippolis, E., Mamchaoui, K., Ferrazzi, F., & Engel, F. B. (2021) · eLife · doi:10.7554/elife.65672 · Cited by 20 · see citing works
SMYD3 promotes aerobic glycolysis in diffuse large B-cell lymphoma via H3K4me3-mediated PKM2 transcription
Tian, T., Li, J., Shi, D., Zeng, Y.-P., Yu, B., Li, X., Wei, P., & Zhou, X. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05208-7 · Cited by 20 · see citing works
The emerging roles of histone demethylases in cancers
Tong, D., Tang, Y., & Zhong, P. (2024) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10160-9 · Cited by 20 · see citing works
“Genes encoding the histone demethy-lases KDM5C and KDM6A were identified as cancer-driving genes [271].”
Avasimibe inhibits the proliferation, migration and invasion of glioma cells by suppressing linc00339
Luo, Y., Liu, L., Li, X., & Shi, Y. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110508 · Cited by 20 · see citing works
Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer
Novillo, A., Fernández‐Santander, A., Gaibar, M., Galán, M. Á., Romero‐Lorca, A., Abdellaoui-Soussi, F. E., & Arco, P. G. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.633233 · Cited by 21 · see citing works
“Indeed, in the PANCAN study, CHD4 was identified as one of the 12 most important cancer-driving genes involved in chromatin epigenetics (29, 30).”
Background
Establishment of prognostic risk model and drug sensitivity based on prognostic related genes of esophageal cancer
Dai, J., Reyimu, A., Sun, A., Duoji, Z., Zhou, W., Song, L., Hu, S., Dai, W., & Xu, X. (2022) · Scientific Reports · doi:10.1038/s41598-022-11760-1 · Cited by 19 · see citing works
Histone demethylase KDM6A coordinating with KMT2B regulates self-renewal and chemoresistance of non-small cell lung cancer stem cells
Chen, Z., Qi, Y., Shen, J., & Chen, Z. (2023) · Translational Oncology · doi:10.1016/j.tranon.2023.101778 · Cited by 19 · see citing works
Epigenetic modifications in early stage lung cancer: pathogenesis, biomarkers, and early diagnosis
Bi, L., Wang, X., Li, J., Li, W., & Wang, Z. (2025) · MedComm · doi:10.1002/mco2.70080 · Cited by 18 · see citing works
“161 Phosphorylation, that is, phosphorylation modifications can regulate the interaction of histones with other proteins and affect gene expression.”
AEBP1 Promotes Glioblastoma Progression and Activates the Classical NF-κB Pathway
Guo, K., Song, L., Chang, J.-Y., Cao, P., & Liu, Q. (2020) · Behavioural Neurology · doi:10.1155/2020/8890452 · Cited by 18 · see citing works
The Interplay between Dysregulated Metabolism and Epigenetics in Cancer
Bassal, M. A. (2023) · Biomolecules · doi:10.3390/biom13060944 · Cited by 19 · see citing works
α-Ketoglutarate supplementation and NAD+ modulation enhance metabolic rewiring and radiosensitization in SLC25A1 inhibited cancer cells
Xiang, K., Kunin, M., Larafa, S., Busch, M. A., Dünker, N., Jendrossek, V., & Matschke, J. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01805-x · Cited by 18 · see citing works
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Authors: Chang, S., Yim, S., & Park, H.
Affiliations: University of Seoul (KR)
Corresponding author: Park, Hyunsung
ORCID: Chang, Soojeong
Yim, Sujin
Park, Hyunsung
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 · 2018: 1
FWCI: 2.46
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor, 19 d)
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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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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