Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics

Copeland, Robert A.; Moyer, Mikel P.; Richon, Victoria M.

doi:10.1038/onc.2012.552

Cited by 67 publications

(59 citation statements)

References 68 publications

(94 reference statements)

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“…Cancer genomic sequencing campaigns have led to the identification of recurrent genomic abnormalities in genes that encode for chromatin-modifying enzymes (2)(3)(4)(5)(6), supporting the concept that cancer cells utilize the manipulation of chromatin structure as one means to invoke transcriptional programs that prevent differentiation and promote proliferation. The emergence of individual KMTs and KDMs as candidate oncology targets has spurred significant drug discovery efforts with the goal to identify small-molecule inhibitors of these enzymes for cancer therapeutic applications (1,7,8).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes

et al. 2016

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Lysine-specific demethylase 1 (KDM1A) is a transcriptional coregulator that can function in both the activation and repression of gene expression, depending upon context. KDM1A plays an important role in hematopoiesis and was identified as a dependency factor in leukemia stem cell populations. Therefore, we investigated the consequences of inhibiting KDM1A in a panel of cell lines representing all acute myelogenous leukemia (AML) subtypes using selective, reversible and irreversible KDM1A smallmolecule inhibitors. Cell models of AML, CML, and T-ALL were potently affected by KDM1A inhibition, and cells bearing RUNX1-RUNX1T1 (AML1-ETO) translocations were especially among the most sensitive. RNAi-mediated silencing of KDM1A also effectively suppressed growth of RUNX1-RUNX1T1-containing cell lines. Furthermore, pharmacologic inhibition of KDM1A resulted in complete abrogation of tumor growth in an AML xenograft model harboring RUNX1-RUNX1T1 translocations. We unexpectedly found that KDM1A-targeting compounds not only inhibited the catalytic activity of the enzyme, but evicted KDM1A from target genes. Accordingly, compound-mediated KDM1A eviction was associated with elevated levels of local histone H3 lysine 4 dimethylation, and increased target gene expression, which was further accompanied by cellular differentiation and induction of cell death. Finally, our finding that KDM1A inhibitors effectively synergize with multiple conventional as well as candidate anti-AML agents affords a framework for potential future clinical application. Cancer Res; 76(7); 1975-88. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes

et al. 2016

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“…Dysregulation of histone methylation can result in reprogramming of gene expression networks and has been associated with diverse disease states, including cancer (4,5,7). Accordingly, enzymes regulating lysine methylation have emerged as a group of promising drug targets (7,10,11).…”

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confidence: 99%

A Chemical Proteomics Approach for Global Analysis of Lysine Monomethylome Profiling *

Cheng

Sun

et al. 2015

Molecular & Cellular Proteomics

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Methylation of lysine residues on histone proteins is known to play an important role in chromatin structure and function. However, non-histone protein substrates of this modification remain largely unknown. An effective approach for system-wide analysis of protein lysine methylation, particularly lysine monomethylation, is lacking. Here we describe a chemical proteomics approach for global screening for monomethyllysine substrates, involving chemical propionylation of monomethylated lysine, affinity enrichment of the modified monomethylated peptides, and HPLC/MS/MS analysis. Using this approach, we identified with high confidence 446 lysine monomethylation sites in 398 proteins, including three previously unknown histone monomethylation marks, representing the largest data set of protein lysine monomethylation described to date. Our data not only confirms previously discovered lysine methylation substrates in the nucleus and spliceosome, but also reveals new substrates associated with diverse biological processes. This method hence offers a powerful approach for dynamic study of protein lysine monomethylation under diverse cellular conditions and in human diseases. Molecular & Cellular

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“…The PMTs constitute an interesting target class for cancer therapeutics both because of the critical role these enzymes play in controlling cellular programs of gene transcription and because, increasingly, bioinformatic surveillance of cancer genome databases are showing that a number of these enzymes are implicated in specific human cancers (5,8); in a recent review, for example, Copeland listed over 10 PMTs for which genetic alterations are found in specific human cancers (8).…”

Section: Introductionmentioning

confidence: 99%

“…Among these various histone modifications (Fig. 1A), methylation of lysine and arginine residues seems to play a particularly important role in control of gene transcription programs (3)(4)(5). These modifications are catalyzed by a class of group-transfer enzymes known as the protein methyltransferases (PMT; refs.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, small-molecule PMT inhibitors of various binding modalities have been reported: S-adenosyl methionine competitive, methyl acceptor competitive, noncompetitive, etc. (5,8). This diversity of inhibitor-binding modalities distinguishes the PMTs from other group-transfer enzymes that have been targeted for cancer therapies (e.g., the kinases) and may allow greater flexibility in choosing inhibitors that offer the greatest chance for clinical translation (12).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Pathways: Protein Methyltransferases in Cancer

Copeland

2013

Clinical Cancer Research

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The protein methyltransferases (PMT) constitute a large and important class of enzymes that catalyze sitespecific methylation of lysine or arginine residues on histones and other proteins. Site-specific histone methylation is a critical component of chromatin regulation of gene transcription-a pathway that is often genetically altered in human cancers. Oncogenic alterations (e.g., mutations, chromosomal translocations, and others) of PMTs, or of associated proteins, have been found to confer unique dependencies of cancer cells on the activity of specific PMTs. Examples of potent, selective small-molecule inhibitors of specific PMTs are reviewed that have been shown to kill cancers cells bearing such oncogenic alterations, while having minimal effect on proliferation of nonaltered cells. Selective inhibitors of the PMTs, DOT1L and EZH2, have entered phase I clinical studies and additional examples of selective PMT inhibitors are likely to enter the clinic soon. The current state of efforts toward clinical testing of selective PMT inhibitors as personalized cancer therapeutics is reviewed here.

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Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics

Cited by 67 publications

References 68 publications

Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes

Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes

A Chemical Proteomics Approach for Global Analysis of Lysine Monomethylome Profiling *

Molecular Pathways: Protein Methyltransferases in Cancer

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