Conserved Antagonism between JMJD2A/KDM4A and HP1γ during Cell Cycle Progression

Black, Joshua C.; Allen, Andrew M.; Rechem, Capucine Van; Forbes, Emily K.; Longworth, Michelle S.; Tschöp, Katrin; Rinehart, Claire A.; Quiton, Jonathan; Walsh, Ryan; Smallwood, Andrea; Dyson, Nicholas J.; Whetstine, Johnathan R.

doi:10.1016/j.molcel.2010.11.008

Cited by 134 publications

(175 citation statements)

References 46 publications

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“…It has been suggested that the JMJD2A histone demethylase plays a major role in the regulation of apoptosis. Specifically, several studies have demonstrated that the depletion of JMJD2A increases p53-dependent apoptosis (41)(42)(43). The findings of the present study showing a substantial reduction in JMJD2A protein expression concomitant with an increase in p53 protein levels in the DFO-treated MCF-7 cells are in accord with this suggestion.…”

Section: Mcf-7supporting

confidence: 91%

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Pogribny

Tryndyak

Pogribna

et al. 2013

International Journal of Oncology

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Abstract. Iron plays a vital role in the normal functioning of cells via the regulation of essential cellular metabolic reactions, including several DNA and histone-modifying proteins. The metabolic status of iron and the regulation of epige netic mechanisms are well-balanced and tightly controlled in normal cells; however, in cancer cells these processes are profoundly disturbed. Cancer-related abnormalities in iron metabolism have been corrected through the use of iron-chelating agents, which cause an inhibition of DNA synthesis, G 1 -S phase arrest, an inhibition of epithelial-to-mesenchymal transition, and the activation of apoptosis. In the present study, we show that, in addition to these well-studied molecular mechanisms, the treatment of wild-type TP53 MCF-7 and mutant TP53 MDA-MB-231 human breast cancer cells with desferrioxamine (DFO), a model iron chelator, causes significant epigenetic alterations at the global and gene-specific levels. Specifically, DFO treatment decreased the protein levels of the histone H3 lysine 9 demethylase, Jumonji domain-containing protein 2A (JMJD2A), in the MCF-7 and MDA-MB-231 cells and down-regulated the levels of the histone H3 lysine 4 demethylase, lysine-specific demethylase 1 (LSD1), in the MDA-MB-231 cells. These changes were accompanied by alterations in corresponding metabolically sensitive histone marks. Additionally, we demonstrate that DFO treatment activates apoptotic programs in MCF-7 and MDA-MB-231 cancer cells and enhances their sensitivity to the chemotherapeutic agents, doxorubicin and cisplatin; however, the mechanisms underlying this activation differ. The induction of apoptosis in wild-type TP53 MCF-7 cells was p53-dependent, triggered mainly by the down-regulation of the JMJD2A histone demethylase, while in mutant TP53 MDA-MB-231 cells, the activation of the p53-independent apoptotic program was driven predominantly by the epigenetic up-regulation of p21. IntroductionA growing body of evidence indicates the existence of an intimate link between the metabolic status and epigenetic regulation of cells (1,2). This is exemplified by the fact that a variety of small molecules involved in intercellular metabolism, including adenosine triphosphate, S-adenosylmethionine, nicotinamide adenine dinucleotide, flavin adenine dinucleotide, folate, acetyl coenzyme A, α-ketoglutarate and iron, are essential for the proper maintenance of the cellular epigenome.Iron is an essential trace element for normal cellular function. In addition to its significance in controlling a variety of cellular processes, including proliferation, DNA synthesis and repair, and mitochondrial electron transport, which are essential for the accurate maintenance of normal cellular homeostasis, iron plays a key regulatory role in the functioning of DNA and histone-modifying proteins (3,4). Specifically, the Jumonji domain-containing histone demethylase (JHDM) family, which catalyzes the demethylation of tri-and dimethylated lysine 9 and lysine 36 residues in histone H3 (5,6) and ten-eleven tra...

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Section: Mcf-7supporting

confidence: 91%

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Pogribny

Tryndyak

Pogribna

et al. 2013

International Journal of Oncology

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“…Recently, Black and colleagues (Black et al 2010) demonstrated that CBX3, along with a histone demethylase, plays a role in cell cycle regulation in Caenorhabditis elegans and human cells. Additionally, CBX3 has been implicated in controlling levels of primordial germ cells (PGCs) in mouse embryos via cell cycle regulation and apoptosis (Abe et al 2011).…”

Section: Discussionmentioning

confidence: 99%

CBX3 regulates efficient RNA processing genome-wide

Smallwood¹,

Hon²,

Jin³

et al. 2012

Genome Res.

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CBX5, CBX1, and CBX3 (HP1α, β, and γ, respectively) play an evolutionarily conserved role in the formation and maintenance of heterochromatin. In addition, CBX5, CBX1, and CBX3 may also participate in transcriptional regulation of genes. Recently, CBX3 binding to the bodies of a subset of genes has been observed in human and murine cells. However, the generality of this phenomenon and the role CBX3 may play in this context are unknown. Genome-wide localization analysis reveals CBX3 binding at genic regions, which strongly correlates with gene activity across multiple cell types. Depletion of CBX3 resulted in down-regulation of a subset of target genes. Loss of CBX3 binding leads to a more dramatic accumulation of unspliced nascent transcripts. In addition, we observed defective recruitment of splicing factors, including SNRNP70, to CBX3 target genes. Collectively, our data suggest a role for CBX3 in aiding in efficient cotranscriptional RNA processing.

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“…In addition, KDM4A plays a critical role in genome replication and stability (6,47). Overexpression of KDM4A leads to accelerated passage through S phase, correlating with increased chromatin accessibility, in human cells, while mutation of the Caenorhabditis elegans KDM4A ortholog leads to reduced rates of S phase and DNA damage (6).…”

mentioning

confidence: 99%

SCF^FBXO22 Regulates Histone H3 Lysine 9 and 36 Methylation Levels by Targeting Histone Demethylase KDM4A for Ubiquitin-Mediated Proteasomal Degradation

Tan

Lim

Harper

2011

Molecular and Cellular Biology

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Reversible methylation of lysine residues has emerged as a central mechanism for epigenetic regulation and is a component of the "histone code," which engenders histones with gene regulatory information. KDM4A is a histone demethylase that targets tri-and dimethylation marks on histone H3 lysines 9 and 36. While the abundance of KDM4A oscillates in the cell cycle, little is known how this enzyme is regulated to achieve targeted effects on specific histone residues in chromatin. Here, we report that a previously unstudied SCF FBXO22 ubiquitin ligase complex controls the activity of KDM4A by targeting it for proteasomal turnover. FBXO22 functions as a receptor for KDM4A by recognizing its catalytic JmjN/JmjC domains via its intracellular signal transduction (FIST) domain. Modulation of FBXO22 levels by RNA interference or overexpression leads to increased or decreased levels of KDM4A, respectively. Changes in KDM4A abundance correlate with alterations in histone H3 lysine 9 and 36 methylation levels, and transcription of a KDM4A target gene, ASCL2. Taken together, these results demonstrate that SCF FBXO22 regulates changes in histone H3 marks and cognate transcriptional control pathways by controlling KDM4A levels, and they suggest a potential role for FBXO22 in development, differentiation, and disease through spatial and temporal control of KDM4A activity.Histones undergo many posttranslational modifications, including acetylation, methylation, phosphorylation, and ubiquitylation (8,17,41). These modifications are governed by enzymes that can add or remove these marks, and they are interpreted by proteins containing specific recognition modules whose action on chromatin alters the transcriptional properties or fate of the cell. Histone methylation typically occurs on lysine and arginine residues, and the extent (mono-, di-, or trimethylation) and position of methylation on histones are associated with often opposing biological outcomes (52). Histone methylation is a posttranslational modification regulated by two classes of proteins, histone methyltransferases and histone demethylases, which can add or remove the mark, respectively, often in a spatially and temporally regulated manner. As a result of its role in key cellular processes, misregulation of histone methylation is associated with human diseases, including cancer (33). Despite clear biological roles for histone methyltransferases and demethylases, to date little is known about how these enzymes are regulated, especially at the posttranslational level.

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Conserved Antagonism between JMJD2A/KDM4A and HP1γ during Cell Cycle Progression

Cited by 134 publications

References 46 publications

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

CBX3 regulates efficient RNA processing genome-wide

SCF^FBXO22 Regulates Histone H3 Lysine 9 and 36 Methylation Levels by Targeting Histone Demethylase KDM4A for Ubiquitin-Mediated Proteasomal Degradation

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Conserved Antagonism between JMJD2A/KDM4A and HP1γ during Cell Cycle Progression

Cited by 134 publications

References 46 publications

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

CBX3 regulates efficient RNA processing genome-wide

SCFFBXO22 Regulates Histone H3 Lysine 9 and 36 Methylation Levels by Targeting Histone Demethylase KDM4A for Ubiquitin-Mediated Proteasomal Degradation

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SCF^FBXO22 Regulates Histone H3 Lysine 9 and 36 Methylation Levels by Targeting Histone Demethylase KDM4A for Ubiquitin-Mediated Proteasomal Degradation