Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting protein lysine methylation and demethylation in cancers.

ABSTRACT: During the last decade, we saw an explosion of studies investigating the role of lysine methylation/demethylation of histones and non-histone proteins, such as p53, NF-kappaB, and E2F1. These 'Ying-Yang' post-translational modifications are important to fine-tuning the activity of these proteins. Lysine methylation and demethylation are catalyzed by protein lysine methyltransferases (PKMTs) and protein lysine demethylases (PKDMs). PKMTs, PKDMs, and their substrates have been shown to play important roles in cancers. Although the underlying mechanisms of tumorigenesis are still largely unknown, growing evidence is starting to link aberrant regulation of methylation to tumorigenesis. This review focuses on summarizing the recent progress in understanding of the function of protein lysine methylation, and in the discovery of small molecule inhibitors for PKMTs and PKDMs. We also discuss the potential and the caveats of targeting protein lysine methylation for the treatment of cancer.

SUBMITTER: He Y

PROVIDER: S-EPMC3244655 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Targeting protein lysine methylation and demethylation in cancers.

He Yunlong Y Korboukh Ilia I Jin Jian J Huang Jing J

Acta biochimica et biophysica Sinica 20120101 1

During the last decade, we saw an explosion of studies investigating the role of lysine methylation/demethylation of histones and non-histone proteins, such as p53, NF-kappaB, and E2F1. These 'Ying-Yang' post-translational modifications are important to fine-tuning the activity of these proteins. Lysine methylation and demethylation are catalyzed by protein lysine methyltransferases (PKMTs) and protein lysine demethylases (PKDMs). PKMTs, PKDMs, and their substrates have been shown to play import ...[more]

PMID: 22194015

Similar Datasets

Structural dynamics of protein lysine methylation and demethylation.

Project description:Lysine methylation plays a central role in the "histone code" that regulates chromatin structure, impacts transcription, and responds to DNA damage. A single lysine can be mono-, di-, tri-methylated, or unmethylated, with different functional consequences for each of the four forms. This review (written in the early 2006) described structural aspects of methylation of histone lysine residues by two enzyme families with entirely different structural scaffolding (the SET proteins and Dot1p), and the protein motifs that recognize (decode) these methyl-lysine signals. We also discuss the recently discovered protein lysine demethylating enzymes (LSD1 and JmjC domains).

| S-EPMC2588418 | biostudies-literature

Investigating d-lysine stereochemistry for epigenetic methylation, demethylation and recognition.

Project description:Histone lysine methylation is regulated by N?-methyltransferases, demethylases, and N?-methyl lysine binding proteins. Thermodynamic, catalytic and computational studies were carried out to investigate the interaction of three epigenetic protein classes with synthetic histone substrates containing l- and d-lysine residues. The results reveal that out of the three classes, N?-methyl lysine binding proteins are superior in accepting lysines with the d-configuration.

| S-EPMC6345366 | biostudies-literature

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

Project description: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.

| S-EPMC8035164 | biostudies-literature

Transcriptional regulation of 15-lipoxygenase expression by histone h3 lysine 4 methylation/demethylation.

Project description:15-Lipoxygenase-1 (15-LOX-1) oxidizes polyunsaturated fatty acids to a rich spectrum of biologically active metabolites and is implicated in physiological membrane remodelling, inflammation and apoptosis. Its deregulation is involved in the pathogenesis of diverse cancer and immune diseases. Recent experimental evidence reveals that dynamic histone methylation/demethylation mediated by histone methyltransferases and demethylases plays a critical role in regulation of chromatin remodelling and gene expression. In the present study, we compared the histone 3 lysine 4 (H3-K4) methylation status of the 15-LOX-1 promoter region of the two Hodgkin lymphoma (HL) cell lines L1236 and L428 with abundant and undetectable 15-LOX-1 expression, respectively. We identified a potential role of H3-K4 methylation in positive regulation of 15-LOX-1 transcription. Furthermore, we found that histone methyltransferase SMYD3 inhibition reduced 15-LOX-1 expression by decreasing promoter activity in L1236 cells. SMYD3 knock down in these cells abolished di-/trimethylation of H3-K4, attenuated the occupancy by the transactivator STAT6, and led to diminished histone H3 acetylation at the 15-LOX-1 promoter. In contrast, inhibition of SMCX, a JmjC-domain-containing H3-K4 tri-demethylase, upregulated 15-LOX-1 expression through induction of H3-K4 trimethylation, histone acetylation and STAT6 recruitment at the 15-LOX-1 promoter in L428 cells. In addition, we observed strong SMYD3 expression in the prostate cancer cell line LNCaP and its inhibition led to decreased 15-LOX-1 expression. Taken together, our data suggest that regulation of histone methylation/demethylation at the 15-LOX-1 promoter is important in 15-LOX-1 expression.

| S-EPMC3532411 | biostudies-literature

Chemical tools targeting readers of lysine methylation.

Project description:Reader domains that recognize methylated lysine and arginine residues on histones play a role in the recruitment, stabilization, and regulation of chromatin regulatory proteins. Targeting reader proteins with small molecule and peptidomimetic inhibitors has enabled the elucidation of the structure and function of specific domains and uncovered their role in diseases. Recent progress towards chemical probes that target readers of lysine methylation, including the Royal family and plant homeodomains (PHD), is discussed here. We highlight recently developed covalent cyclic peptide inhibitors of a plant homeodomain. Additionally, inhibitors targeting previously untargeted Tudor domains and chromodomains are discussed.

| S-EPMC10264141 | biostudies-literature

Azalysine analogues as probes for protein lysine deacetylation and demethylation.

Project description:Reversible lysine acetylation and methylation regulate the function of a wide variety of proteins, including histones. Here, we have synthesized azalysine-containing peptides in acetylated and unacetylated forms as chemical probes of the histone deacetylases (HDAC8, Sir2Tm, and SIRT1) and the histone demethylase, LSD1. We have shown that the acetyl-azalysine modification is a fairly efficient substrate for the sirtuins, but a weaker substrate for HDAC8, a classical HDAC. In addition to deacetylation by sirtuins, the acetyl-azalysine analogue generates a novel ADP-ribose adduct that was characterized by mass spectrometry, Western blot analysis, and nuclear magnetic resonance spectroscopy. This peptide-ADP-ribose adduct is proposed to correspond to a derailed reaction intermediate, providing unique evidence for the direct 2'-hydroxyl attack on the O-alkylimidate intermediate that is formed in the course of sirtuin catalyzed deacetylation. An unacetylated azalysine-containing H3 peptide proved to be a potent inhibitor of the LSD1 demethylase, forming an FAD adduct characteristic of previously reported related structures, providing a new chemical probe for mechanistic analysis.

| S-EPMC3313494 | biostudies-literature

Structural insights into histone lysine demethylation.

Project description:Posttranslational modifications of histone tails are crucial epigenetic marks that regulate diverse cellular processes. Histone lysine methylation activates or represses transcription, depending on the site and degree of these modifications. Two classes of histone lysine demethylases remove histone methylation. Lysine demethylase 1 (KDM1, also known as LSD1) is a flavin adenine dinucleotide (FAD)-containing enzyme that removes mono-/di-methylation. The Jumonji C-terminal domain (JmjC) family of histone demethylases uses Fe(2+) and ?-ketoglutarate as cofactors to remove all methylation states. Structural studies have provided insights into the overall architecture, the catalytic mechanism, and the substrate specificity of histone demethylases. Here, we review these exciting advances in the structure biology of histone demethylases and discuss the general principles applicable to other histone-modifying enzymes.

| S-EPMC3010374 | biostudies-literature

The functional diversity of protein lysine methylation.

Project description:Large-scale characterization of post-translational modifications (PTMs), such as phosphorylation, acetylation and ubiquitination, has highlighted their importance in the regulation of a myriad of signaling events. While high-throughput technologies have tremendously helped cataloguing the proteins modified by these PTMs, the identification of lysine-methylated proteins, a PTM involving the transfer of one, two or three methyl groups to the ?-amine of a lysine side chain, has lagged behind. While the initial findings were focused on the methylation of histone proteins, several studies have recently identified novel non-histone lysine-methylated proteins. This review provides a compilation of all lysine methylation sites reported to date. We also present key examples showing the impact of lysine methylation and discuss the circuitries wired by this important PTM.

| S-EPMC4023394 | biostudies-literature

Intrinsic protein disorder in histone lysine methylation.

Project description:UnlabelledHistone lysine methyltransferases (HKMTs), catalyze mono-, di- and trimethylation of lysine residues, resulting in a regulatory pattern that controls gene expression. Their involvement in many different cellular processes and diseases makes HKMTs an intensively studied protein group, but scientific interest so far has been concentrated mostly on their catalytic domains. In this work we set out to analyze the structural heterogeneity of human HKMTs and found that many contain long intrinsically disordered regions (IDRs) that are conserved through vertebrate species. Our predictions show that these IDRs contain several linear motifs and conserved putative binding sites that harbor cancer-related SNPs. Although there are only limited data available in the literature, some of the predicted binding regions overlap with interacting segments identified experimentally. The importance of a disordered binding site is illustrated through the example of the ternary complex between MLL1, menin and LEDGF/p75. Our suggestion is that intrinsic protein disorder plays an as yet unrecognized role in epigenetic regulation, which needs to be further elucidated through structural and functional studies aimed specifically at the disordered regions of HKMTs.ReviewersThis article was reviewed by Arne Elofsson and Piotr Zielenkiewicz.

| S-EPMC4928265 | biostudies-literature

Chemical and Biochemical Perspectives of Protein Lysine Methylation.

Project description:Protein lysine methylation is a distinct posttranslational modification that causes minimal changes in the size and electrostatic status of lysine residues. Lysine methylation plays essential roles in regulating fates and functions of target proteins in an epigenetic manner. As a result, substrates and degrees (free versus mono/di/tri) of protein lysine methylation are orchestrated within cells by balanced activities of protein lysine methyltransferases (PKMTs) and demethylases (KDMs). Their dysregulation is often associated with neurological disorders, developmental abnormalities, or cancer. Methyllysine-containing proteins can be recognized by downstream effector proteins, which contain methyllysine reader domains, to relay their biological functions. While numerous efforts have been made to annotate biological roles of protein lysine methylation, limited work has been done to uncover mechanisms associated with this modification at a molecular or atomic level. Given distinct biophysical and biochemical properties of methyllysine, this review will focus on chemical and biochemical aspects in addition, recognition, and removal of this posttranslational mark. Chemical and biophysical methods to profile PKMT substrates will be discussed along with classification of PKMT inhibitors for accurate perturbation of methyltransferase activities. Semisynthesis of methyllysine-containing proteins will also be covered given the critical need for these reagents to unambiguously define functional roles of protein lysine methylation.

| S-EPMC6668730 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data