Table 1.
Protein lysine methyltransferases dysregulated in cancer
| Family name | Enzyme name | Substrate | Changes in cancer | Cancer type | Specific inhibitors |
|---|---|---|---|---|---|
| SET and MYND domain‐containing proteins (SMYD) | SMYD2 (KMT3C) | Histone H3, p53, RB1, PARP1, HSP90AB1, PTEN, ER‐α | Overexpression DNA amplification | Bladder cancer, breast cancer, cervical cancer, esophageal cancer, CRC, HCC, head and neck cancer, lymphoma, ovarian cancer, pancreatic cancer, RCC | AZ505 (preclinical) LLY‐507 (preclinical) A‐893 (preclinical) |
| SMYD3 (KMT3E) | Histone H3, histone H4, VEGFR1, MAP3K2 | Overexpression DNA amplification | Breast cancer, CCC, cervical cancer, CRC, esophageal cancer, gastric cancer, HCC, lung cancer, MTC, pancreatic cancer, prostate cancer | BCI‐121 (preclinical) EPZ031686 (preclinical) | |
| Polycomb complex | EZH2 (KMT6) | Histone H2B, histone H3, RORα, STAT3 | Overexpression DNA amplification GOF missense mutations (Y641, A677, A687) LOF mutations | AML, bladder cancer, breast cancer, CCC, CML, CRC, esophageal cancer, glioblastoma, lymphoma, NSCLC, SCLC, T‐ALL, osteosarcoma, RCC | GSK126 (preclinical) EPZ005687 (preclinical) EPZ‐6438 (phase I/II)† |
| Nuclear receptor‐binding SET‐domain proteins (NSD) | NSD1 (KMT3B) | Histone H3, NF‐κB | Chromosomal translocation (NUP98‐NSD1: t(5;11)(q35;p15)) DNA amplification | AML, glioblastoma, lung cancer, multiple myeloma | – |
| WHSC1 (MMSET and NSD2) | Histone H3 | Chromosomal translocation (IGH‐WHSC1: t(4;14)(p16;q32)) Overexpression DNA amplification | Bladder cancer, breast cancer, CCC, CML, esophageal cancer, HCC, multiple myeloma, NSCLC, SCLC, osteosarcoma, prostate cancer and RCC | MCTP39 (preclinical) LEM‐06 (preclinical) | |
| WHSC1L1 (NSD3) | Histone H3 | Chromosomal translocation (NUP98‐WHSC1L1: t(8;11)(p11.2;p15), WHSC1L1‐NUT: t(8;15)(p11.2;q14)), Overexpression, DNA amplification | AML, bladder cancer, breast cancer, NUT, SCLC, lymphoma | – | |
| SET‐domain containing proteins (SETD) | SETD1A (KMT2F) | Histone H3, HSP70 | Overexpression | Bladder cancer, breast cancer, CRC, HCC, lung cancer, RCC | – |
| SETD8 (KMT5A) | Histone H4, PCNA | Overexpression | Bladder cancer, CML, HCC, NSCLC, prostate cancer, SCLC | UNC0379 (preclinical) | |
| Suppressor of Variegation 3–9 Homolog | SUV39H2 (KMT1B) | Histone H2AX, histone H3, LSD1 | Overexpression | ALL, Bladder cancer, cervical cancer, esophageal cancer, NSCLC, osteosarcoma, prostate cancer, STT | – |
| Euchromatic histone‐lysine N‐methyltransferase | EHMT2 (KMT1C, G9a) | Histone H3, C/EBPβ | Overexpression | AML, bladder cancer, breast cancer, CCC, CML, esophageal cancer, NSCLC, SCLC, prostate cancer | BIX‐01294 (preclinical) UNC0638 (preclinical) |
| DOT1‐like histone H3K79 methyltransferase | DOT1L (KMT4) | Histone H3 | DOT1L physically interacts with MLL fusion proteins | MLL | EPZ004777 (preclinical) EPZ‐5676 (phase I)† |
| MLL family | MLL (KMT2A) | Histone H3 | Chromosomal translocation | AML | – |
| MLL2 (KMT2D) | Histone H3 | Overexpression (mRNA) Mutations | Bladder cancer, breast cancer, CRC, lung cancer, melanoma, MLL | – | |
| MLL3 (KMT2C) | Histone H3 | Point mutations Small insertions/deletions | Breast cancer, esophagus cancer, glioblastoma, melanoma, MLL, pancreas cancer, stomach cancer | – |
†Inhibitors currently undergoing clinical trials. –, not particular. ALL, acute lymphoblastic leukemia; AML; acute myeloid leukemia; CCC, cholangiocarcinoma; C/EBPβ, CCAAT/enhancer binding protein; CML, chronic myelogenous leukemia; CRC, colorectal cancer; DOT1L, disruptor of telomeric silencing 1‐like; ERα, estrogen receptor α; GOF, gain‐of‐function; HCC, hepatocellular carcinoma; HSP, heat shock protein; LOF, loss‐of‐function; MLL, mixed‐lineage leukemia; MTC, medullary thyroid cancer; NF‐κB, nuclear factor‐κB; NSCLC, non‐small‐cell lung carcinoma; NUT, NUT midline carcinoma; PARP, poly(ADP‐ribose) polymerase; PTEN, phosphatase and tensin homolog; RB, retinoblastoma; RCC, renal cell carcinoma; RORα, retinoid‐related orphan receptor α; SCLC, small‐cell lung carcinoma; STAT, signal transducer and activator of transcription; STT, soft tissue tumors; T‐ALL, T‐cell acute lymphoblastic leukemia; VEGFR, vascular endothelial growth factor receptor.