The Emerging Role of Epigenetic Modifiers in Repair of DNA Damage Associated with Chronic Inflammatory Diseases

At sites of chronic inflammation epithelial cells are exposed to high levels of reactive oxygen species (ROS), which can contribute to the initiation and development of many different human cancers. Aberrant epigenetic alterations that cause transcriptional silencing of tumor suppressor genes are also implicated in many diseases associated with inflammation, including cancer. However, it is not clear how altered epigenetic gene silencing is initiated during chronic inflammation. The high level of ROS at sites of inflammation is known to induce oxidative DNA damage in surrounding epithelial cells. Furthermore, DNA damage is known to trigger several responses, including recruitment of DNA repair proteins, transcriptional repression, chromatin modifications and other cell signaling events. Recruitment of epigenetic modifiers to chromatin in response to DNA damage results in transient covalent modifications to chromatin such as histone ubiquitination, acetylation and methylation and DNA methylation. DNA damage also alters non-coding RNA expression. All of these alterations have the potential to alter gene expression at sites of damage. Typically, these modifications and gene transcription are restored back to normal once the repair of the DNA damage is completed. However, chronic inflammation may induce sustained DNA damage and DNA damage responses that result in these transient covalent chromatin modifications becoming mitotically stable epigenetic alterations. Understanding how epigenetic alterations are initiated during chronic inflammation will allow us to develop pharmaceutical strategies to prevent or treat chronic inflammation-induced cancer. This review will focus on types of DNA damage and epigenetic alterations associated with chronic inflammatory diseases, the types of DNA damage and transient covalent chromatin modifications induced by inflammation and oxidative DNA damage and how these modifications may result in epigenetic alterations

Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis

Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared with normal epithelium and noninflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis

DNA methyltransferase inhibition reduces inflammation-induced colon tumorigenesis

Chronic inflammation is strongly associated with an increased risk of developing colorectal cancer. DNA hypermethylation of CpG islands alters the expression of genes in cancer cells and plays an important role in carcinogenesis. Chronic inflammation is also associated with DNA methylation alterations and in a mouse model of inflammation-induced colon tumorigenesis, we previously demonstrated that inflammation-induced tumours have 203 unique regions with DNA hypermethylation compared to uninflamed epithelium. To determine if altering inflammation-induced DNA hypermethylation reduces tumorigenesis, we used the same mouse model and treated mice with the DNA methyltransferase (DNMT) inhibitor decitabine (DAC) throughout the tumorigenesis time frame. DAC treatment caused a significant reduction in colon tumorigenesis. The tumours that did form after DAC treatment had reduced inflammation-specific DNA hypermethylation and alteration of expression of associated candidate genes. When compared, inflammation-induced tumours from control (PBS-treated) mice were enriched for cell proliferation associated gene expression pathways whereas inflammation-induced tumours from DAC-treated mice were enriched for interferon gene signatures. To further understand the altered tumorigenesis, we derived tumoroids from the different tumour types. Interestingly, tumoroids derived from inflammation-induced tumours from control mice maintained many of the inflammation-induced DNA hypermethylation alterations and had higher levels of DNA hypermethylation at these regions than tumoroids from DAC-treated mice. Importantly, tumoroids derived from inflammation-induced tumours from the DAC-treated mice proliferated more slowly than those derived from the inflammation-induced tumours from control mice. These studies suggest that inhibition of inflammation-induced DNA hypermethylation may be an effective strategy to reduce inflammation-induced tumorigenesis

Doxorubicin-induced death in tumour cells and cardiomyocytes: is autophagy the key to improving future clinical outcomes?

Objectives: Doxorubicin, a commonly used frontline chemotherapeutic agent for cancer, is not without side-effects. The original thinking that the drug causes necrosis in tumours has largely given way to its link with apoptosis over the past two decades. Key findings: More recently, major biomarkers such as AMPK, p53 and Bcl-2 have been identified as important to apoptosis induction by doxorubicin. It is Bcl-2 and its interaction with Beclin-1 that has refocussed research attention on doxorubicin, albeit this time for its ability to induce autophagy. Autophagy can be either anticancerous or procancerous however, so it is critical that the reasons for which cancer cells undergo this type of cell biological event be clearly identified for future exploitation. Summary: Taking a step back from treating patients with large doses of doxorubicin, which causes toxicity to the heart amongst other organs, and further research with this drug's molecular signalling in not only neoplastic but normal cells, may indeed redefine the way doxorubicin is used clinically and potentially lead to better neoplastic disease management