Aberrant Activity of Histone-Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis

Abstract

KMT2 (histone-lysine N-methyltransferase subclass 2) complexes methylate lysine 4 on the histone H3 tail at gene promoters and gene enhancers and, thus, control the process of gene transcription. These complexes not only play an essential role in normal development but have also been described as involved in the aberrant growth of tissues. KMT2 mutations resulting from the rearrangements of the KMT2A (MLL1) gene at 11q23 are associated with pediatric mixed-lineage leukemias, and recent studies demonstrate that KMT2 genes are frequently mutated in many types of human cancers. Moreover, other components of the KMT2 complexes have been reported to contribute to oncogenesis. This review summarizes the recent advances in our knowledge of the role of KMT2 complexes in cell transformation. In addition, it discusses the therapeutic targeting of different components of the KMT2 complexes.

Keywords: COMPASS; COMPASS-like; H3K4 methylation; cancer; chromatin; epigenetics; histone–lysine N-methyltransferase 2; oncogenesis.

Figure 1

(a) Domain structure of the KMT2 family and core subunits of the KMT2 complexes. The numbers indicate the number of amino acids. KMT, histone–lysine N-methyltransferase; ASH2L, absent, small, or homeotic 2-like; DPY30, Dumpy-30; RBBP5, retinoblastoma-binding protein 5; WDR5, WD repeat-containing protein 5; AT-hook, adenosine-thymidine-hook; CXXC, Zinc finger-CXXC domain; FYRN/FYRC, phenylalanine and tyrosine-rich region (N- and C-terminal); HMG, high mobility group; HWH, helix-wing-helix domain; N-SET, N-terminal of SET; PHD, plant homeodomain; Post-SET, C-terminal of SET; RRM, RNA recognition motif; SDI, Sdc1-Dpy-30 interaction; SET, Su(var)3-9, Enhancer-of-zeste and Trithorax; SPRY, SPla and the ryanodine receptor domain; and WD repeat, tryptophan-aspartic acid repeat. (b) The structure of the KMT2 complex. The enzyme and the core subunits of the complex are shown in the diagram. The interactions between individual subunits are marked with blue lines. Subunits specific to individual KMT2 complexes, not shown in the figure, interact with the amino terminus of the KMT2s. WIN motif, WDR5 interaction motif.

Figure 2

Specialization of COMPASS and COMPASS-like complexes in mammals. The KMT2F/KMT2G complexes, referred to as COMPASS complexes, are most similar to the yeast Set1 complex. These complexes are mainly responsible for bulk H3K4me3 genome-wide. The KMT2A/KMT2B and KMT2C/KMT2D complexes are referred to as COMPASS-like and are most similar to the Drosophila Trithorax complex and Drosophila Trithorax-related protein, respectively. KMT2A/KMT2B complexes are required for the H3K4 tri- and dimethylation in less than 5% of promoters and mainly regulate developmental genes. KMT2C/KMT2D complexes occupy enhancers and are responsible for H3K4 monomethylation.

Figure 3

Mechanisms of H3K4 methyltransferase recruitment to chromatin. KMT2 complexes are recruited and stabilized on chromatin by a combination of mechanisms: (a) interactions with sequence-specific transcription factors, (b) association with the basal transcriptional machinery, (c) interaction with long noncoding RNAs (lncRNAs), (d) recognition of histone modification, and (e) direct interaction with DNA. For references, see the text.

Figure 4

Known writers, readers, and erasers of H3K4 methylation.

Figure 5

Wild-type KMT2A (MLL) and diverse KMT2A-fusion proteins (MLL-FPs). (a) Schematic representation of the wild-type (wt) KMT2A structure. Each domain is labeled in black capital letters, while interacting proteins are marked in rounded yellow-shaded rectangles. A cleavage site recognized by taspase 1 is annotated with a blue arrow. Three major functional parts of the protein responsible for targeting, regulation, and transactivation are also indicated. The protein product of the MLL/KMT2A gene is composed of 3969 amino acids and contains many domains that are involved in the regulation of gene transcription [122]. These include an AT-hook motif-binding DNA [123], a CXXC domain rich in cysteines [124,125], homeodomain (PHD) finger motifs [126], a bromodomain (BRD) [127], and a potent transcriptional activation domain (TAD) located between the amino acids 2829 and 2883 [128,129]. The KMT2A protein also contains a WIN motif responsible for the interaction with WDR5 and maintaining the H3K4me2 activity of the MLL core complex in vitro [130,131,132]. At the carboxy-terminal part of the protein, there is a SET domain conferring the histone methyltransferase activity of MLL [133,134]. A natural maturation course of MLL includes its proteolysis into two fragments, MLL-N and MLL-C, which then form a complex in vivo [135,136]. Two motifs—namely, FYRC and FYRN—are indispensable for heterodimerization between the terminal fragments of cleaved MLL, which can interact with many other proteins to form multiunit complexes required for transcriptional coactivator activity [134,137]. In MLL-FPs, many N-terminal domains, such as PHD, FYRN, FYRC, and SET, are lost. A detailed description is provided in the main text. (b) The most frequent rearrangements of KMT2A (MLL) in MLL. The data were obtained from Meyer et al. [99]. The three most frequent translocations of MLL are with AF4, AF9, and ENL. (c) Composition of the wt MLL COMPASS-like complex containing MLL-N and MLL-C. Core subunits (DPY30, ASH2L, WDR5, and RBBP5); Menin; and LEDGF are shown. (d) Composition of an MLL-FP complex. It contains MLL-FP, DOT1L, SEC, Menin, and LEDGF—the last two proteins are present in both wt and rearranged complexes.