Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease

Abstract

Protein lysine methylation is a crucial post-translational modification that regulates the functions of both histone and non-histone proteins. Deregulation of the enzymes or ‘writers’ of protein lysine methylation, lysine methyltransferases (KMTs), is implicated in the cause of many diseases, including cancer, mental health disorders and developmental disorders. Over the past decade, significant advances have been made in developing drugs to target KMTs that are involved in histone methylation and epigenetic regulation. The first of these inhibitors, tazemetostat, was recently approved for the treatment of epithelioid sarcoma and follicular lymphoma, and several more are in clinical and preclinical evaluation. Beyond chromatin, the many KMTs that regulate protein synthesis and other fundamental biological processes are emerging as promising new targets for drug development to treat diverse diseases.

Fig. 1: Overview of lysine methylation.
Fig. 2: EZH2, H3K27 methylation and tumorigenesis.
Fig. 3: DOT1L, H3K79 methylation and MLL-r leukaemia.
Fig. 4: Selective inhibitors of lysine methyltransferases in preclinical development.
Fig. 5: SMYD3 promotes RAS-driven tumorigenesis.
Fig. 6: RAS-driven cancer dependency on METTL13-mediated protein synthesis.

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Acknowledgements

This work was supported in part by grants from the NIH to K.P.B. (K00CA212435), O.G. (R01 CA236118) and J.J. (R01CA218600, R01CA230854, R01GM122749 and R01HD088626).

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The authors contributed equally to all aspects of the article.

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Correspondence to Jian Jin or Or Gozani.

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Competing interests

O.G. is a co-founder of EpiCypher and Athelas Therapeutics. J.J. and H.Ü.K. are inventors of patent applications filed by the Icahn School of Medicine at Mount Sinai. J.J. is a consultant of Cullgen and Accent Therapeutics, a scientific advisory board member of Petra Pharma Corporation and an equity shareholder of Cullgen. K.P.B. is an employee at Genentech.

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Supplementary information

Glossary

Reader domains

Modules on proteins that bind to post-translationally modified lysine residues on other proteins in a manner that is dependent on the immediate surrounding sequence and the state of methylation on the lysine.

Writers of protein lysine methylation

Enzymes that catalyse the addition of one, two or three methyl moieties to the ε-nitrogen of lysine residues.

Nucleosome

The fundamental building block of chromatin, which consists of ~146 base pairs of DNA wrapped around a protein core unit made of two copies each of histones H2A, H2B, H3 and H4.

Chromatin-remodelling complexes

Large ATP-dependent multisubunit protein complexes that evict, load, alter or otherwise move nucleosomes on DNA to control DNA accessibility.

Transcriptional elongation factors

Proteins that regulate the elongation step in gene transcription, which occurs after transcription is stably initiated and before transcription termination.

Mixed-lineage leukaemia (MLL) genes

MLL1, MLL2, MLL3 and MLL4 encode four distinct lysine methyltransferases that catalyse methylation at histone H3 K4; MLL1 was originally identified as a gene involved in a recurrent chromosomal translocation in the neoplasm mixed-lineage leukaemia.

Fusion protein

Chimeric proteins that result from the fusion of genes from different chromosomes during chromosomal translocations. They often have a new, non-physiologic activity that can unbalance cells and drive cancer pathogenesis.

A-site

The aminoacyl site, or A-site, on the ribosome is the entry site for amino acid–tRNA molecules to bind and for proper base pairing between the mRNA codon and the tRNA anticodon during the elongation step of protein synthesis.

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Bhat, K.P., Ümit Kaniskan, H., Jin, J. et al. Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease. Nat Rev Drug Discov (2021). https://doi.org/10.1038/s41573-020-00108-x

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