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

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Aberrant Activity of Histone–Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis International Journal of Molecular Sciences Review Aberrant Activity of Histone–Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis Elzbieta Poreba 1,* , Krzysztof Lesniewicz 2 and Julia Durzynska 1,* 1 Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, ul. Uniwersytetu Pozna´nskiego6, 61-614 Pozna´n,Poland 2 Department of Molecular and Cellular Biology, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, ul. Uniwersytetu Pozna´nskiego6, 61-614 Pozna´n,Poland; [email protected] * Correspondence: [email protected] (E.P.); [email protected] (J.D.); Tel.: +48-61-829-5857 (E.P.) Received: 19 November 2020; Accepted: 6 December 2020; Published: 8 December 2020 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: histone–lysine N-methyltransferase 2; COMPASS; COMPASS-like; H3K4 methylation; oncogenesis; cancer; epigenetics; chromatin 1. Introduction In the past two decades, efforts have been made to create a comprehensive and universal description of common traits of cancer cells. This gave rise to a new term—cancer hallmark—that reflects each of the intrinsic characteristics of a cancer cell not found in normal cells. Although a vigorous debate is still taking place, it can be agreed upon that cancer cells are independent of growth and antigrowth stimuli. These cells can evade apoptosis and replicate in a limitless manner and, hence, become immortal. Cancer cells also induce angiogenesis for a better supply of nutrients and are capable of spreading to different sites of the body (metastasis). Furthermore, they can reprogram energy metabolism, escape the immune response system, and promote inflammation. The underlying conditions are mutations and genome instability, which allow for the establishment of all cancer hallmarks [1–4]. However, the genetic landscape of cells undergoing transformation is only one part of the story, as the acquired knowledge of epigenetic modifications has helped us understand their crucial importance and contribution to virtually all classic hallmarks of cancer [5]. Recent studies based on the high-throughput sequencing of genomes, epigenomes, and transcriptomes have provided us with enormous data pointing to the relationship between cancer development and mutations in genes encoding epigenetic modifiers. Abnormal histone methylation resulting from gene mutation, translocation, or the deregulated expression of histone methyltransferases has been frequently observed in cancers. Depending on the histone and the modified residue, the process of methylation plays various Int. J. Mol. Sci. 2020, 21, 9340; doi:10.3390/ijms21249340 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 37 Int. J. Mol. Sci. 2020, 21, 9340 2 of 37 methylation plays various biological roles. The methylation of lysine 4 on histone H3 is associated with transcriptional activation and is catalyzed by histone methyltransferases classified as KMT2s biological(lysine-specific roles. methyltransferases The methylation of subclass lysine 4 on 2) histone[6]. H3K4 H3 trimethylation is associated with (H3K4me3) transcriptional is characteristic activation andof accessible is catalyzed gene by histonepromoters, methyltransferases whereas H3K4 classified monomethylation as KMT2s (lysine-specific(H3K4me1) occurs methyltransferases in enhancer subclasselements 2)[7–9]. [6]. H3K4 trimethylation (H3K4me3) is characteristic of accessible gene promoters, whereasThis H3K4 review monomethylation aims to present the (H3K4me1) most recent occurs advances in enhancer in our elementsunderstanding [7–9]. of the structure and role ofThis KMT2 review complexes aims to in present cellular the transformation most recent. advancesThe oncogenic in our outcomes understanding of mutations of the in structure KMT2s, andas well role as of in KMT2 the core complexes subunits in of cellular the KMT2 transformation. complexes, Theare oncogenicdiscussed. outcomesIn addition, of mutationsa number inof KMT2s,molecularas wellstrategies as in thetargeting core subunits different of the compon KMT2 complexes,ents of the are KMT2 discussed. complexes In addition, with aanticancer number of moleculartherapeutic strategies potential targeting are described different in detail. components of the KMT2 complexes with anticancer therapeutic potential are described in detail. 2. Structure of the KMT2 Complexes 2. Structure of the KMT2 Complexes KMT2s are the main H3K4 methyltransferases that regulate gene transcription. The KMT2 familyKMT2s is highly are the conserved main H3K4 in methyltransferaseseukaryotes. While thatthree regulate subgroups gene transcription.of KMT2s, each The with KMT2 a familysingle isrepresentative, highly conserved are inpresent eukaryotes. in Drosophila While three melanogaster subgroups—trithorax of KMT2s, (Trx), each trithorax-related with a single representative, (Trr), and areSet1—two present paralogs in Drosophila of each melanogaster subgroup—trithorax appeared (Trx),in humans trithorax-related during evolution. (Trr), and Human Set1—two cells paralogs contain oftwo each Trx-related subgroup KMT2s appeared (KMT2A in humans and KMT2B), during tw evolution.o Trr-related Human KMT2s cells (KMT2C contain and two KMT2D), Trx-related and KMT2stwo Set1-related (KMT2A KMT2s and KMT2B), (KMT2F two and Trr-related KMT2G) KMT2s(Figure (KMT2C1). Although and KMT2D),KMT2E was and initially two Set1-related classified KMT2sunder the (KMT2F KMT2 andfamily, KMT2G) it was (Figureidentified1). to Although be more KMT2E homologous was initially to yeast classified SET3 (SET under domain- the KMT2containing family, protein it was 3) and identified SET4 (SET to bedomain-containing more homologous protein to yeast 4) and SET3 Drosophila (SET domain-containing CG9007 (encoding proteinthe protein 3) and “UpSET”) SET4 (SET [10–12]. domain-containing Moreover, unlike protein the 4)other and KMT2sDrosophila presentCG9007 in humans, (encoding KMT2E the protein does “UpSET”)not exhibit[ intrinsic10–12]. Moreover, methyltransferase unlike the activity other toward KMT2s histone present substrates in humans, [12]. KMT2E does not exhibit intrinsic methyltransferase activity toward histone substrates [12]. Figure 1. (a) Domain structure of the KMT2 family and core subunits of the KMT2 complexes. The numbers Figure 1. (a) Domain structure of the KMT2 family and core subunits of the KMT2 complexes. The indicate the number of amino acids. KMT, histone–lysine N-methyltransferase; ASH2L, absent, numbers indicate the number of amino acids. KMT, histone–lysine N-methyltransferase; ASH2L, small, or homeotic 2-like; DPY30, Dumpy-30; RBBP5, retinoblastoma-binding protein 5; WDR5, absent, small, or homeotic 2-like; DPY30, Dumpy-30; RBBP5, retinoblastoma-binding protein 5; WD repeat-containing protein 5; AT-hook, adenosine-thymidine-hook; CXXC, Zinc finger-CXXC WDR5, WD repeat-containing protein 5; AT-hook, adenosine-thymidine-hook; CXXC, Zinc finger- domain; FYRN/FYRC, phenylalanine and tyrosine-rich region (N- and C-terminal); HMG, high mobility CXXC domain; FYRN/FYRC, phenylalanine and tyrosine-rich region (N- and C-terminal); HMG, high group; HWH, helix-wing-helix domain; N-SET, N-terminal of SET; PHD, plant homeodomain; Post-SET, C-terminalmobility group; of SET; HWH, RRM, RNAhelix-wing-helix recognition motif;domain; SDI, N-SET, Sdc1-Dpy-30 N-terminal interaction; of SET; SET, PHD, Su(var)3-9, plant motif Enhancer-of-zestehomeodomain; Post-SET, and Trithorax; C-terminal SPRY, of SPla SET; and RRM, the ryanodineRNA recognition receptor domain;; SDI, and Sdc1-Dpy-30 WD repeat, tryptophan-asparticinteraction; SET, Su(var)3-9, acid repeat. Enhancer-of-zeste (b) The structure and Trithorax; of the KMT2 SPRY, complex. SPla and The the enzyme ryanodine and receptor the core subunitsdomain; and of the WD complex repeat, aretryptophan-aspartic shown in the diagram. acid repeat. The interactions (b) The structure between of the individual KMT2 complex. subunits The are markedenzyme withand the blue core lines. subunits Subunits of the specific complex to individual are shown KMT2 in the complexes, diagram. The not interactions shown in the between figure, interactindividual with subunits the amino are marked terminus with of the blue KMT2s. lines. Su WINbunits motif, specific WDR5 to interactionindividual motif.KMT2 complexes, not shown in the figure, interact with the amino terminus of the KMT2s. WIN motif, WDR5 interaction motif. Int. J. Mol. Sci. 2020, 21, 9340 3 of 37 The KMT2s function in large multi-subunit complexes, which, in vertebrates, are often referred to as COMPASS or COMPASS-like complexes (COMplex of Proteins ASsociated with Set1). While
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