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.

Keywords: :

• breast cancer
• chronic inflammation
• epigenetics
• gastric cancer
• immune-checkpoint blocker
• lung cancer
• melanoma
• MYC
• prostate cancer
• synthetic lethality

Financial & competing interests disclosure

This study was financially supported in part by a grant-in-aid for the Knowledgebase Project from the M Katoh’s Fund. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This study was financially supported in part by a grant-in-aid for the Knowledgebase Project from the M Katoh’s Fund. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.