Methylation of DNA repair genes and the efficacy of DNA targeted anticancer treatment

Julsing, Joris R.; Peters, Godefridus J.

doi:10.7243/2052-6199-2-3

Cited by 13 publications

(9 citation statements)

References 108 publications

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“…The maintenance of cellular integrity depends on the efficiency of multiple specific DNA repair pathways (reviewed in [ 47 ]) which are crucial in protecting against genomic instability, a characteristic of tumor development [ 48 ]. Genotoxic exposure to carcinogens such as tobacco often results in DNA damage that represents an important mechanism of OPSCC etiology [ 49 ].…”

Section: Dna Methylationmentioning

confidence: 99%

Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors

et al. 2017

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In the last years, the explosion of high throughput sequencing technologies has enabled epigenome-wide analyses, allowing a more comprehensive overview of the oropharyngeal squamous cell carcinoma (OPSCC) epigenetic landscape. In this setting, the cellular pathways contributing to the neoplastic phenotype, including cell cycle regulation, cell signaling, DNA repair, and apoptosis have been demonstrated to be potential targets of epigenetic alterations in OPSCC. Of note, it has becoming increasingly clear that HPV infection and OPSCC lifestyle risk factors differently drive the epigenetic machinery in cancer cells. Epigenetic changes, including DNA methylation, histone modifications, and non-coding RNA expression, can be used as powerful and reliable tools for early diagnosis of OPSCC patients and improve prognostication. Since epigenetic changes are dynamic and reversible, epigenetic enzymes may also represent suitable targets for the development of more effective OPSCC therapeutic strategies. Thus, this review will focus on the main known epigenetic modifications that can occur in OPSCC and their exploitation as potential biomarkers and therapeutic targets. Furthermore, we will address epigenetic alterations to OPSCC risk factors, with a particular focus on HPV infection, tobacco exposure, and heavy alcohol consumption.

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Section: Dna Methylationmentioning

confidence: 99%

Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors

et al. 2017

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“…There are three established DNMTs responsible for DNA methylation: DNMT1, DNMT3a, and DNMT3b. DNMT1 are responsible for maintaining the established correct methylation pattern through cell division in DNA replication [41]. In the DNMT3 family, DNMT3a and DNMT3b are involved in establishing de novo methylation patterns during embryogenesis and associate with the replication fork in the late S-phase during replication [41, 42].…”

Section: Epigenetics Of Gastric Cancermentioning

confidence: 99%

“…DNMT1 are responsible for maintaining the established correct methylation pattern through cell division in DNA replication [41]. In the DNMT3 family, DNMT3a and DNMT3b are involved in establishing de novo methylation patterns during embryogenesis and associate with the replication fork in the late S-phase during replication [41, 42]. Also DNMT3L is responsible for de novo methylation but remains catalytically inactive and might cause gene repression even without DNA methylation [43].…”

Section: Epigenetics Of Gastric Cancermentioning

confidence: 99%

“…Global hypomethylation of the genome contributes to oncogene activation and genomic instability which leads to mutagenesis and cancer development. Alternatively local hypermethylation of tumour suppressor genes leads to oncogenesis [41, 42]. DNA methylation, once established, can be inherited by the next generations making it a stable epigenetic mark and hence the most studied epigenetic modification [37, 42, 43].…”

Section: Epigenetics Of Gastric Cancermentioning

confidence: 99%

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Gastric cancer and related epigenetic alterations

Patel

Roy

Ravi

2017

ecancer

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Gastric cancer, a malignant and highly proliferative condition, has significantly affected a large population around the globe and is known to be caused by various factors including genetic, epigenetic, and environmental influences. Though the global trend of these cancers is declining, an increase in its frequency is still a threat because of changing lifestyles and dietary habits. However, genetic and epigenetic alterations related to gastric cancers also have an equivalent contribution towards carcinogenic development. DNA methylation is one of the major forms of epigenetic modification which plays a significant role in gastric carcinogenesis. Methylation leads to inactivation of some of the most important genes like DNA repair genes, cell cycle regulators, apoptotic genes, transcriptional regulators, and signalling pathway regulators; which subsequently cause uncontrolled proliferation of cells. Mutations in these genes can be used as suitable prognostic markers for early diagnosis of the disease, since late diagnosis of gastric cancers has a huge negative impact on overall patient survival. In this review, we focus on the important epigenetic mutations that contribute to the development of gastric cancer and the molecular pathogenesis underlying each of them. Methylation, acetylation, and histone modifications play an integral role in the onset of genomic instability, one of the many contributory factors to gastric cancer. This article also covers the constraints of incomplete knowledge of epigenetic factors influencing gastric cancer, thus throwing light on our understanding of the disease.

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“…Both normal and neoplastic cells have several types of repair pathways, usually starting with the recognition and excision of the lesion, and then insertion of a new nucleotide. Regulation of several of these repair enzymes is mediated through methylation of the gene or activation of various protein kinases[ 150 ]. Given the complex biology underlying the interactions between the targeted agent and chemoradiation, comprehensive preclinical investigations are critical to design the rational combination[ 148 ].…”

Section: Indirect Alteration Of Akt Signaling and Its Modulationmentioning

confidence: 99%

Role of Akt signaling in resistance to DNA-targeted therapy

Avan

Narayan

Giovannetti

et al. 2016

WJCO

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The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.

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Methylation of DNA repair genes and the efficacy of DNA targeted anticancer treatment

Cited by 13 publications

References 108 publications

Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors

Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors

Gastric cancer and related epigenetic alterations

Role of Akt signaling in resistance to DNA-targeted therapy

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