title: Mutation spectra of histone methyltransferases with canonical SET domains and EZH2-targeted therapy.
abstract: Germline mutations in canonical SET-methyltransferases have been identified in autism and intellectual disability syndromes and gain-of-function somatic alterations in EZH2, MLL3, NSD1, WHSC1 (NSD2) and WHSC1L1 (NSD3) in cancer. EZH2 interacts with AR, ERα, β-catenin, FOXP3, NF-κB, PRC2, REST and SNAI2, resulting in context-dependent transcriptional activation and repression. Pharmacological EZH2 inhibitors are currently in clinical trials for the treatment of B-cell lymphomas and solid tumors. EZH2 inhibitors might also be applicable in the treatment of SWI/SNF-mutant cancers, reflecting the reciprocal expression of and functional overlap between EZH2 and SMARCA4. Because of the risks for autoimmune diseases, cognitive impairment, cardiomyopathy and myelodysplastic syndrome, EZH2 inhibitors should be utilized for cancer treatment in patients receiving long-term surveillance but not for cancer chemoprevention.
authors.affiliation: Department of Omics Network, National Cancer Center, 5-1-1 Tsukiji, Chuo-ward, Tokyo 104-0045, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Katoh
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D010802:Phylogeny; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C452979:KMT2C protein, human; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2
keywords: MYC; breast cancer; chronic inflammation; epigenetics; gastric cancer; immune-checkpoint blocker; lung cancer; melanoma; prostate cancer; synthetic lethality