Table 1.
Histone Lysine Demethylases (KDMs): Specificity, Transcriptional Effects, and Potential Links to Cancer
| Cluster | Names | Demethylase Activity | Transcriptional Effects | Cancer Alterations and Possible Mechanisms | Putative Cancer Roles | References |
|---|---|---|---|---|---|---|
| KDM1 | KDM1A; LSD1; BHC110; AOF2 | H3K4me2/1 | Repression | Overexpression in breast, small cell lung, colorectal, prostate, neuroblastoma, and bladder cancer | Putative oncogene | 35-37 |
| H3K9me2/1 | Activation | |||||
| KDM1B; LSD2; AOF1 | H3K4me2/1 | Repression | NR | NR | ||
| KDM2 | KDM2A; JHDM1A; FBXL11 | H3K36me2/1 | Repression | Reduced expression in prostate cancer; suppression of NF-κB-dependent growth of colon cancer cells; effects on chromosomal segregation | Context-dependent pro- and anti-oncogenic functions | 76-84 |
| KDM2B; JHDM1B; FBXL10 | H3K36me2/1 | Repression | Overexpression in lymphomas and adenocarcinomas; downregulation in glioblastoma multiform; mutation in hematological tumors; cell protection against ultraviolet (UV)–induced apoptosis, oxidative stress, and spontaneous mutagenesis | Context-dependent pro- and anti-oncogenic functions | 76-84 | |
| H3K4me3 (?) | Repression | 74, 76 | ||||
| KDM3 | KDM3A; JMJD1A; JHDM2A; TSGA | H3K9me2/1 | Activation | Co-activator of androgen receptor (AR)–mediated transcription; under hypoxia increases a subset of hypoxia-inducible genes enhancing tumor growth | NR | 85-90, 93 |
| KDM3B; JMJD1B; JHDM2B; 5qNCA | H3K9me2/1 | Activation | 5q31 (JMJD1B) frequent deletion in cancer | Candidate tumor suppressor | 91, 92 | |
| KDM3C; JMJD1C; JHDM2C; TRIP8 | NR | Reduced expression in breast cancer | Candidate tumor suppressor | 91, 92 | ||
| KDM4 | KDM4A; JMJD2A; JHDM3A | H3K9me3/2 | Activation | Overexpression in prostate cancer | Putative oncogene | 26, 94-102 |
| H3K36me3/2 | Repression | |||||
| KDM4B; JMJD2B; JHDM3B | H3K9me3/2 | Activation | Overexpression in prostate cancer | Putative oncogene | 26, 94-102 | |
| H3K36me3/2 | Repression | |||||
| KDM4C; JMJD2C; JHDM3C; GASC1 | H3K9me3/2 | Activation | Overexpression/amplification in prostate cancer, esophageal squamous cell carcinoma, desmoplastic medulloblastoma, metastatic lung sarcomatoid carcinoma, mucosa-associated lymphoid tissue (MALT) lymphoma, and breast cancer; increasing genomic instability; transcriptional activation of oncogenes (e.g., NOTCH1, MDM2) and of AR target genes | Putative oncogene | 26, 94-102 | |
| H3K36me3/2 | Repression | |||||
| KDM5 | KDM5A; JARID1A; RBP2 | H3K4me3/2 | Repression | Translocation: NUP98-JARID1A fusion protein; overexpression in gastric cancer; key effector of pRB-mediated cell cycle withdrawal and differentiation; elevated expression in drug-tolerant subpopulation of cancer cells | Conflicting reports and likely context-dependent pro- and anti-oncogenic functions | 103-111 |
| KDM5B; JARID1B; PLU-1 | H3K4me3/2 | Repression | Overexpression in breast, testis, prostate, ovary, and esophageal cancer; silencing of tumor suppressor genes (e.g., BRCA1, CAV1, HOXA5) | Putative oncogene | 112-114 | |
| KDM5C; JARID1C; SMCX | H3K4me3/2 | Repression | Regulation of human papilloma virus (HPV) oncogene expression | NR | 67, 116 | |
| KDM5D; JARID1D; SMCY | H3K4me3/2 | Repression | NR | 67 | ||
| KDM6 | KDM6A; UTX | H3K27me3/2 | Activation | Downregulation; inactivating somatic mutations in multiple myeloma, esophageal squamous cell carcinomas, and renal cell carcinomas; transcriptional activation of pRB binding proteins contributing to the pRB-mediated cell cycle arrest | Candidate tumor suppressor | 117-120, 123, 126, 127 |
| KDM6B; JMJD3 | H3K27me3/2 | Activation | Downregulation in subsets of human cancers; 17p13.1 (JMJD3) frequent deletion in cancer; transcriptional activation of INK4A/ARF region promoting senescence | Candidate tumor suppressor | 117-120, 124, 125, 128 |
NR, not reported.