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).