The emerging role of epigenetic modifiers in repair of DNA damage associated with chronic inflammatory diseases

Ding, Ning; Maiuri, Ashley R.; O’Hagan, Heather M.

doi:10.1016/j.mrrev.2017.09.005

Cited by 26 publications

(28 citation statements)

References 165 publications

(176 reference statements)

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“…Balance between proand anti-inflammatory mechanisms is responsible for tissue homeostasis (17). However, an abnormal imbalance is often associated with the development of cancer accompanied by an inflammatory response (18)(19)(20)(21). Inflammatory responses are mediated by specific cytokines and chemokines commonly expressed by immune cells; however, cancer cells have also been reported to produce cytokines and chemokines in order to promote tumorigenesis in an inflammatory microenvironment (22).…”

Section: Introductionmentioning

confidence: 99%

CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel

et al. 2018

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Abstract. Lung cancer is one of the most common malignant tumor types globally. Acquisition of chemoresistance in lung cancer cells is the primary cause of chemotherapy failure. Inflammatory chemokine C-C motif chemokine ligand 2 (CCL2) has been reported to be involved in the progression of cancer and drug resistance. However, its function in docetaxel (DTX) resistance of lung cancer remains unclear. In the present study, the mechanism underlying DTX-induced drug resistance was investigated. Reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that DTX treatment increased the mRNA and protein expression of CCL2 in lung cancer A549 cells. CCL2 was knocked down by small interfering RNA or was overexpressed by recombinant CCL2 lentivirus, and cell viability was determined. An MTT assay indicated that CCL2 downregulation decreased the viability of A549 cells and augmented the DTX-induced cytotoxicity, whereas CCL2 upregulation protected A549 cells from DTX-induced cytotoxicity. Additionally, it was revealed that CCL2 overexpression activated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling and inhibited apoptosis-associated protein caspase-3 activation and B-cell lymphoma 2 (Bcl-2) phosphorylation at Ser 70 induced by DTX, and enhanced DTX-induced Bcl-2-associated death promoter phosphorylation at Ser 112 . PI3K/AKT inhibitor LY294002 restored DTX-induced caspase-3 activation and Bcl-2 phosphorylation, reversed the effect of CCL2 on the viability of A549 cells and enhanced DTX-induced cytotoxicity. These results demonstrated that chemoresistance may be mediated by cell stress responses involving CCL2 expression, suggesting that CCL2 may be a potential target for enhancing the therapeutic effect of DTX in lung cancer.

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Section: Introductionmentioning

confidence: 99%

CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel

et al. 2018

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“…It has also been suggested that an expanded CTG repeat itself is responsible for induction of methylation 29 The connection between MSH2-induced repeat instability and upstream methylation may be indirect through a third partner. In an in vitro human model in which DNA double strand breaks (DSBs) were induced, it has been suggested that the MMR pathway recruits epigenetic modifiers such as the DNA methyl transferase DNMT1 at DNA damage sites in order to contribute to the DNA repair process [34][35][36] . After a successful repair, demethylase activity possibly restores the methylated site to its original unmethylated state 36 .…”

Section: Discussionmentioning

confidence: 99%

“…In an in vitro human model in which DNA double strand breaks (DSBs) were induced, it has been suggested that the MMR pathway recruits epigenetic modifiers such as the DNA methyl transferase DNMT1 at DNA damage sites in order to contribute to the DNA repair process [34][35][36] . After a successful repair, demethylase activity possibly restores the methylated site to its original unmethylated state 36 . In our MSH2WT hESC lines carrying a CTG expansion, CpG methylation flanking the CTG repeat is maintained and even increased over time in cell culture as in VUB19WT-SC1 and VUB19WT-SC2.…”

Section: Discussionmentioning

confidence: 99%

MSH2knock-down shows CTG repeat stability and concomitant upstream demethylation at theDMPKlocus in myotonic dystrophy type 1 human embryonic stem cells

Franck

Barbé

Ardui

et al. 2020

Preprint

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Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DMPK gene, where expansion size and somatic mosaicism correlates with disease severity and age of onset. While it is known that the mismatch repair protein MSH2 contributes to the unstable nature of the repeat, its role on other disease-related features, such as CpG methylation upstream of the repeat, is unknown. In this study, we investigated the effect of an MSH2 knock-down (MSH2KD) on both CTG repeat dynamics and CpG methylation pattern in human embryonic stem cells (hESC) carrying the DM1 mutation. Repeat size in MSH2 wild type (MSH2WT) and MSH2KD DM1 hESC was determined by PacBio sequencing and CpG methylation by bisulfite massive parallel sequencing. We found stabilization of the CTG repeat concurrent with a gradual loss of methylation upstream of the repeat in MSH2KD cells, while the repeat continued to expand and upstream methylation remained unchanged in MSH2WT control lines. Repeat instability was re-established and biased towards expansions upon MSH2 transgenic re-expression in MSH2KD lines while upstream methylation was not consistently re-established. We hypothesize that the hypermethylation at the mutant DM1 locus is promoted by the MMR machinery and sustained by a constant DNA repair response, establishing a potential mechanistic link between CTG repeat instability and upstream CpG methylation. Our work represents a first step towards understanding how epigenetic alterations and repair pathways connect and contribute to the DM1 pathology.

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“…Once DNA repair proteins access DNA, “repressive” chromatin modifiers such as histone deacetylases (HDACs) are recruited to “close” the chromatin and repress transcriptional activity. Finally, chromatin is restored back to its original state when repair is completed (Ding et al, ). In response to oxidative DNA damage, we demonstrated that (1) JAK2 is recruited to chromatin, (2) JAK2 interacts with MSH2 and MSH6 in the nucleus, and (3) inhibiting JAK2 alters the chromatin interaction of MSH2, MSH6, DNMT1, and PRC2 members.…”

Section: Discussionmentioning

confidence: 99%

JAK2 regulates mismatch repair protein‐mediated epigenetic alterations in response to oxidative damage

Ding

Miller

Savant

et al. 2019

Environ and Mol Mutagen

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At sites of chronic inflammation epithelial cells undergo aberrant DNA methylation that contributes to tumorigenesis. Inflammation is associated with an increase in reactive oxygen species (ROS) that cause oxidative DNA damage, which has also been linked to epigenetic alterations. We previously demonstrated that in response to ROS, mismatch repair proteins MSH2 and MSH6 recruit epigenetic silencing proteins DNA methyltransferase 1 (DNMT1) and polycomb repressive complex 2 (PRC2) members to sites of DNA damage, resulting in transcriptional repression of tumor suppressor genes (TSGs). However, it was unclear what signal is unique to ROS that results in the chromatin binding of MSH2 and MSH6. Herein, we demonstrate that in response to hydrogen peroxide (H2O2), JAK2 localizes to the nucleus and interacts with MSH2 and MSH6. Inhibition or knockdown of JAK2 reduces the H2O2‐induced chromatin interaction of MSH2, MSH6, DNMT1, and PRC2 members, reduces H2O2‐induced global increase in trimethylation of lysine 27 of histone H3 (H3K27me3), and abrogates oxidative damage‐induced transcriptional repression of candidate TSGs. Moreover, JAK2 mRNA expression is associated with CpG island methylator phenotype (CIMP) status in human colorectal cancer. Our findings provide novel insight into the connection between kinase activation and epigenetic alterations during oxidative damage and inflammation. Environ. Mol. Mutagen. 60:308–319, 2019. © 2018 Wiley Periodicals, Inc.

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The emerging role of epigenetic modifiers in repair of DNA damage associated with chronic inflammatory diseases

Cited by 26 publications

References 165 publications

CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel

CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel

MSH2knock-down shows CTG repeat stability and concomitant upstream demethylation at theDMPKlocus in myotonic dystrophy type 1 human embryonic stem cells

JAK2 regulates mismatch repair protein‐mediated epigenetic alterations in response to oxidative damage

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