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

Our plain-English summary of The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism, by S. Chang, S. Yim, H. Park (Experimental & Molecular Medicine, 2019).

The study

• Authors: S. Chang, S. Yim, H. Park
• Journal: Experimental & Molecular Medicine
• Published: 2019;51(6):1-17
• Type of article: Review
• Cited by: 205 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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 (Table 1). 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. Table 1 Cancer driver genes involved in epigenetics Pathways involved in epigenetics Driver genes Tumor suppressor/oncogene prediction (by 20/20+a) Approved name Activity Cancer typeb Other driver genes in this pathways Histone modification KDM6A tsg Lysine demethylase 6A, UTX H3K27me2/3 demethylase BLCA, HNSC, KIRP, LUSC, PAAD, PANCAN, PRAD PPP6C SETD2 tsg SET domain-containing 2 H3K36 methyl transferase KIRC, KIRP, LGG, LUAD, MESO, PANCAN Chromatin histone modifiers KDM5C tsg Lysine demethylase 5C, JARID1C H3K4me2/3 demethylase KIRC, PANCAN ARID5B, CREBBP, EP300, KANSL1, MEN1, NCOR1, NSD1, SIN3A, WHSC1, ZMYM3 KMT2A tsg Lysine methyltransferase 2A H3K4 methyl transferase PANCAN KMT2B tsg Lysine methyltransferase 2B H3K4 methyl transferase PANCAN, UCEC KMT2C tsg Lysine methyltransferase 2C H3K4 methyl transferase BLCA, BRCA, CESC, PANCAN, UCEC KMT2D tsg Lysine methyltransferase 2D H3K4 methyl transferase BLCA, CESC, DLBC, ESCA, HNSC, LUSC, PANCAN, PRAD Chromatin (other) H3F3A Possible oncogene H3 histone family member 3A, H3.3A PANCAN AJUBA, ASXL1, ASXL2, ATF7IP, BCOR, CHD3, CHD4, CHD8, CTCF, NIPBL, NPM1 H3F3C - H3 histone family member 3C, H3.5 PANCAN HIST1H1E Possible oncogene HIST1H1E, H1.4 DLBC Possible tsg HIST1H1E, H1.4 LIHC Metabolism IDH1 Oncogene Isocitrate dehydrogenase (NADP(+)) 1 NADP-dependent IDH, Cytosolic CHOL, GBM, LAML, LGG, LIHC, PANCAN, PRAD, SKCM - IDH2 Oncogene Isocitrate dehydrogenase (NADP(+)) 2 NADP-dependent IDH, Mitochondrial LAML, LGG, PANCAN Among the 299 driver genes mentioned by Bailey et al.47, only the epigenetics-related pathways have been sorted out a20/20+: Classifies genes as an oncogene, tumor suppressor gene, or as a nondriver gene using Random Forests, http://2020plus.readthedocs.org bBLCA (bladder urothelial carcinoma), BRCA (breast invasive carcinoma), CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma), CHOL (cholangiocarcinoma), DLBC (lymphoid neoplasm diffuse large B-cell lymphoma), ESCA (esophageal carcinoma), GBM (glioblastoma multiforme), HNSC (head and neck squamous cell carcinoma), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma), LAML (acute myeloid leukemia), LGG (brain lower grade glioma), LIHC (liver hepatocellular carcinoma), LUAD (lung adenocarcinoma), LUSC (lung squamous cell carcinoma), MESO (mesothelioma), PAAD (pancreatic adenocarcinoma), PANCAN (Pan-cancer), PRAD (prostate adenocarcinoma), SKCM (skin cutaneous melanoma), THCA (thyroid carcinoma), UCEC (uterine corpus endometrial carcinoma).

In plain English

This article was a review, not a new study. The authors reviewed research on how cancer genes that control chemical tags on histones (proteins that package DNA) interact with tumor metabolism and low oxygen (hypoxia). It did not study asbestos or any exposed group. The review drew on a 2018 Cancer Genome Atlas analysis by Bailey and colleagues identifying 299 cancer driver genes. Of 12 histone-related genes, those for two histone demethylases, JARID1C/KDM5C and UTX/KDM6A, were identified as cancer drivers. A table from that analysis listed mesothelioma among the cancer types for another gene, SETD2, predicted to be a tumor suppressor. The review did not discuss mesothelioma further. The authors described studies showing that mutated IDH1/2 enzymes produce D-2-hydroxyglutarate and hypoxia raises L-2-hydroxyglutarate, both able to inhibit some histone demethylases; they left open whether this relates to the tumor-suppressive roles of JARID1C and UTX. The authors concluded that JARID1C and UTX act as tumor suppressors, that related enzymes act as tumor suppressors or oncogenes depending on cancer type, and that how JARID1C and UTX suppress tumors remains unclear.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published research
• Who was studied: No study population of its own. The review covered published laboratory, animal and genomic studies, including the Cancer Genome Atlas driver-gene analysis by Bailey et al. (299 driver genes), from which only the epigenetics-related genes were listed.
• Exposure: No asbestos or other environmental or occupational exposure was studied. The review concerned IDH1/2 gene mutations, hypoxia and the oncometabolite 2-hydroxyglutarate in relation to histone demethylases.
• Main results:
  • From the Cancer Genome Atlas analysis the review drew on: among 12 driver genes involved in histones, the genes for the histone demethylases JARID1C/KDM5C and UTX/KDM6A were identified as cancer driver genes.
  • In Table 1 (compiled from Bailey et al.), mesothelioma (MESO) was among the cancer types listed for SETD2, an H3K36 methyltransferase predicted to be a tumor suppressor gene. The review did not discuss mesothelioma elsewhere.
  • Studies reviewed reported that mutated IDH1/2 enzymes gain a new activity converting alpha-ketoglutarate to D-2-hydroxyglutarate (D-2HG).
  • Studies reviewed reported that hypoxia induces production of L-2-hydroxyglutarate (L-2HG) in normal and malignant cells.
  • The authors listed as an unsolved question whether this metabolic regulation of histone methylation is related to the tumor-suppressive functions of JARID1C/KDM5C and UTX/KDM6A.
  • Studies reviewed showed that the related enzyme JMJD3 plays contradictory roles, acting as both a tumor suppressor and an oncogene.
• The authors' conclusion: The authors concluded that JARID1C and UTX function as tumor suppressors in various cancers, while JARID1A, 1B, 1D and JMJD3 act as tumor suppressors or oncogenes depending on cancer type. They also concluded that the mechanisms by which JARID1C and UTX suppress tumors remain unclear.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Suppressor Gene, Carcinoma, Squamous Cell Carcinoma, Adenocarcinoma, Neoplasm, Lung Adenocarcinoma, Mesothelioma.

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