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.

a | The lysine methylation reaction is catalysed by lysine methyltransferase (KMT) and reversed by lysine demethylase (KDM), and results in monomethylation, dimethylation and trimethylation of lysine residues. b | The main lysine residues on histones H3 and H4 that are methylated and/or clinically relevant and discussed in this Review are shown. c | Protein Data Bank (PDB) structures of G9a (SET domain family) and disruptor of telomeric silencing 1-like protein (DOT1L) (7β-strand (7βS) domain family) methyltransferases as representative examples of the two known KMT catalytic families. The conserved tyrosine residue in the catalytic pocket in both structures is shown in blue. The cofactor S-adenosyl methionine (SAM) and its by-product S-adenosyl homocysteine (SAH) are shown bound to DOT1L and G9a, respectively.

Fig. 2 |. eZH2, H3K27 methylation and tumorigenesis.

a | Histone H3 K27 (H3K27) methylation activity relative to processivity for wild-type (WT) enhancer of zeste homologue 2 (EZH2) and mutant (MUT) EZH2. b | EZH2 forms a complex with SUZ12, EED and other subunits of Polycomb repressive complex 2 (PRC2) to catalyse H3K27 trimethylation. Normal PRC2 activity is critical for gene regulation during development, and deregulation of PRC2 activity can promote tumorigenesis by pathological silencing of key genes. Inhibitors of EZH2 (EZH2i) or EED (EEDi) block PRC2-mediated methylation in cancer to attenuate tumour development and progression. c | Structures of EZH2 inhibitors, including S-adenosyl methionine (SAM)-competitive PRC2-EZH2 inhibitors in clinical trials, and allosteric inhibitors that disrupt the EED–H3K27me3 interaction. The EZH2 inhibitor tazemetostat is approved by the FDA for treating epithelioid sarcoma and follicular lymphoma after at least two prior systemic therapies.

Fig. 3 |. DoT1L, H3K79 methylation and MLL-r leukaemia.

a | Principal catalytic functions of mixed-lineage leukaemia (MLL) proteins and disruptor of telomeric silencing 1-like protein (DOT1L). b | DOT1L is mislocalized by MLL fusion proteins to catalyse histone H3 K79 dimethylation at non-physiologic loci. Inhibitors of DOT1L, menin–MLL protein interaction and reader domains in the DotCom complex block this activity and could have therapeutic utility. See the main text for details of mechanisms. c | Structures of DOT1L catalytic inhibitors. AF9i, AF9 inhibitor; DOT1Li, DOT1L inhibitor; ENLi, ENL inhibitor; H3K4me1, K4-monomethlylated histone H3; H3K4me3, K4-trimethlylated histone H3; H3K79me2, K79-dimethlylated histone H3; MLL-C, carboxy-terminal side of MLL protein; MLL-N, amino-terminal side of MLL protein; MLL-r, rearrangements in mixed-lineage leukaemia genes.

Fig. 4 |. Selective inhibitors of lysine methyltransferases in preclinical development.

Chemical structures of compounds targeting G9a/G9a-like protein (GLP) (part a), SETD8 (part b), SUV420H1/SUV420H2 (part c), SETD7 (part d) and SMYD2 (part e) are shown.

Fig. 5 |. SMyD3 promotes RAS-driven tumorigenesis.

a | Basic schematic of the RAS–mitogen-activated protein kinase (MAPK) signalling cascade. Under normal conditions, growth factor activation of a receptor tyrosine kinase (RTK) induces RAS to switch from the GDP-bound inactive state to the GTP-bound active state. Constitutively active oncogenic mutant RAS bypasses normal induction, resulting in increased downstream signalling. Mitogen-activated protein kinase kinase kinase 2 (MAP3K2) feeds into RAS–MAPK signalling by phosphorylating and activating MEK1/2. Dephosphorylation of MAP3K2 by protein phosphatase 2A (PP2A) renders it inactive. SMYD3 trimethylation (me3) of MAP3K2 repels PP2A to prevent dephosphorylation, resulting in increased MAP3K2–MEK1/2–extracellular signal-regulated kinase 1/2 (ERK1/2) signalling and promotion of RAS-driven tumorigenesis. b | Structures of SMYD3 inhibitors.

Fig. 6 |. RAS-driven cancer dependency on MeTTL13-mediated protein synthesis.

a | METTL13-mediated dimethylation of EEF1A on K55 increases EEF1A’s intrinsic GTPase activity, resulting in accelerated translation elongation and increased protein synthesis. b | Mutant KRAS-driven cancers become dependent on the METTL13–K55-dimethylated EEF1A axis to maintain high translational rates required for malignant growth. The vulnerability of tumours to METTL13 depletion suggests potential efficacy of METTL13 inhibitors (METTL13i) to treat lethal malignancies. PI3K/mTORi, dual inhibitor of PI3K and mechanistic target of rapamycin.