Mitochondrial DNA Repair through OGG1 Activity Attenuates Breast Cancer Progression and Metastasis

Yuzefovych, Larysa V.; Kahn, Andrea G.; Schuler, Michele A.; Eide, Lars; Arora, Richa; Wilson, Glenn L.; Tan, Ming; Rachek, Lyudmila I.

doi:10.1158/0008-5472.can-15-0692

Cited by 37 publications

(33 citation statements)

References 19 publications

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“…Recently, the mitochondrial DNA repair machinery was reported to be reduced during disease progression and forced expression of mtDNA repair enzymes in mice delayed metastasis (36). Therefore, defects in mtDNA repair, as suggested by the increased steady state level of mtDNA lesions in the UPR mt positive cell lines (Suppl, Fig.…”

Section: Discussionmentioning

confidence: 99%

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Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

et al. 2017

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By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis. However, mtDNA landscapes of all metastatic cells are characterized by activation of the SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPR mt ). The UPR mt promotes a complex transcription program ultimately increasing mitochondrial integrity and fitness in response to oxidative proteotoxic stress. Using SOD2 as a surrogate marker of the UPR mt , we found that in primary breast cancers, SOD2 is significantly increased in metastatic lesions. We propose that the ability of selected mtDNA species to activate the UPR mt is a process that is exploited by cancer cells to maintain mitochondrial fitness and facilitate metastasis.

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Section: Discussionmentioning

confidence: 99%

“…7, sub-population 2). As mtDNA repair capacity has been linked to metastasis (36), the prediction is that the number of mtDNA mutations will increase leading to heteroplasmy (Fig. 7, sub-population 2).…”

Section: Discussionmentioning

confidence: 99%

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

et al. 2017

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“…Dysregulation or loss of OGG1 causes accumulation of oxidative DNA damage [13-15], which is strongly associated with various diseases, including cancer [16]. OGG1 polymorphism have been reported to associate to susceptibility of lung cancer[17-20], pancreatic cancer [21-24], bladder cancer [25-28], breast cancer [29-31], esophageal cancer, colorectal cancer. However, the mechanism about how OGG1 functions in lung cancer has not been reported yet.…”

Section: Introductionmentioning

confidence: 99%

MiR-4673 Modulates Paclitaxel-Induced Oxidative Stress and Loss of Mitochondrial Membrane Potential by Targeting 8-Oxoguanine-DNA Glycosylase-1

Huang

Shi

Huang

et al. 2017

Cell Physiol Biochem

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Background: Our previous study identified a novel microRNA, miR-4673, which is upregulated in A549 cells exposed to paclitaxel (PTX). In this study, we investigated the role of miR-4673 in PTX-induced cytotoxicity. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, apoptosis assay, 5,5’,6,6’-Tetrachloro-1,1’,3,3’-tetraethyl-imidacarbocyanine iodide (JC-1) staining and 2’,7’-Dichlorofluorescein (DCFH) staining were used to evaluate cell viability, apoptosis, mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis and Luciferase reporter assay were used to explore whether 8-oxoguanine-DNA glycosylase-1 (OGG1) is a target gene of miR-4673. Results: Enforced expression of miR-4673 decreased cell viability and increased PTX-induced apoptosis, MMP loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis, which was used to identify potential target of miR-4673, revealed a binding site of miR-4673 in 3’UTR of OGG1. Luciferase reporters assays showed that miR-4673 specifically binds to ‘CUGUUGA’ in 3’UTR of OGG1. Enforced expression of miR-4673 decreased accumulation of OGG1. In addition, silencing OGG1 enhanced inhibitory effects of PTX on apoptosis, MMP loss and ROS generation, which is similar to effects of miR-4673. Moreover, enforced expression of OGG1 compromised promoting effects of miR-4673 on PTX-induced apoptosis, MMP loss and ROS generation. Conclusion: miR-4673 modulates PTX-induced apoptosis, MMP loss and ROS generation by targeting OGG1.

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“…On the other hand, Kleist and colleagues determined that microsatellite instability in hypervariable regions (HVR1, HVR2, and HVR3) within the D-loop region, specifically at positions D310 in HVR2, D514 in HVR3, and D16184 in HVR1, was more frequently associated with lymph node metastases than primary tumors in colorectal cancer (27). In another study, genetic modulation (KO mouse model) of the human DNA repair enzyme 8-oxoguanine DNA glycosylase isoform 1-a (OGG1) protein in mitochondria was protective against increased mtDNA damage and dysfunction (28). Reduced mtDNA damage led to suppressed mitochondrial ROS production and reduced ROS-dependent metastases in a polyoma virus middle T antigen (PyMT) model of breast cancer (28).…”

Section: Mtdna and Metastasismentioning

confidence: 99%

“…In another study, genetic modulation (KO mouse model) of the human DNA repair enzyme 8-oxoguanine DNA glycosylase isoform 1-a (OGG1) protein in mitochondria was protective against increased mtDNA damage and dysfunction (28). Reduced mtDNA damage led to suppressed mitochondrial ROS production and reduced ROS-dependent metastases in a polyoma virus middle T antigen (PyMT) model of breast cancer (28). Thus, these data collectively suggest that alterations in mtDNA that drive cancer metastases may be cancertype dependent, with specific mutations driving metastasis in one cancer type, and the collective mitochondrial genome dictating metastatic susceptibility in another.…”

Section: Mtdna and Metastasismentioning

confidence: 99%

Understanding Mitochondrial Polymorphisms in Cancer

Bussard

Siracusa

2017

Cancer Research

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Alterations in mitochondrial DNA (mtDNA) were once thought to be predominantly innocuous to cell growth. Recent evidence suggests that mtDNA undergo naturally occurring alterations, including mutations and polymorphisms, which profoundly affect the cells in which they appear and contribute to a variety of diseases, including cardiovascular disease, diabetes, and cancer. Furthermore, interplay between mtDNA and nuclear DNA has been found in cancer cells, necessitating consideration of these complex interactions for future studies of cancer mutations and polymorphisms. In this issue of Cancer Research, Vivian and colleagues utilize a unique mouse model, called Mitochondrial Nuclear eXchange mice, that contain the nuclear DNA from one inbred mouse strain, and the mtDNA from a different inbred mouse strain to examine the genomewide nuclear DNA methylation and gene expression patterns of brain tissue. Results demonstrated there were alterations in nuclear DNA expression and DNA methylation driven by mtDNA. These alterations may impact disease pathogenesis. In light of these results, in this review, we highlight alterations in mtDNA, with a specific focus on polymorphisms associated with cancer susceptibility and/or prognosis, mtDNA as cancer biomarkers, and considerations for investigating the role of mtDNA in cancer progression for future studies.

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Mitochondrial DNA Repair through OGG1 Activity Attenuates Breast Cancer Progression and Metastasis

Cited by 37 publications

References 19 publications

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

MiR-4673 Modulates Paclitaxel-Induced Oxidative Stress and Loss of Mitochondrial Membrane Potential by Targeting 8-Oxoguanine-DNA Glycosylase-1

Understanding Mitochondrial Polymorphisms in Cancer

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