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Chronic diseases account for over 60% of all deaths worldwide according to the World Health Organization reports. Majority of cases are triggered by environmental exposures that lead to aberrant changes in the epigenome, specifically, the DNA methylation patterns. These changes result in altered expression of gene networks and activity of signalling pathways. Dietary antioxidants, including catechins, flavonoids, anthocyanins, stilbenes and carotenoids, demonstrate benefits in the prevention and/or support of therapy in chronic diseases. This review provides a comprehensive discussion of potential epigenetic mechanisms of antioxidant compounds in reversing altered patterns of DNA methylation in chronic disease. Antioxidants remodel the DNA methylation patterns through multiple mechanisms, including regulation of epigenetic enzymes and chromatin remodelling complexes. These effects can further contribute to antioxidant properties of the compounds. On the other hand, decrease in oxidative stress itself can impact DNA methylation delivering additional link between antioxidant mechanisms and epigenetic effects of the compounds. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation and composition of the colon microbiota have been associated with colorectal cancer in humans. The human commensal enterotoxigenic Bacteroides fragilis (ETBF) is linked to both inflammatory bowel disease and colorectal cancer and, in our murine model, causes interleukin 17A (IL-17A)-dependent colon tumors. In these studies, we hypothesized that persistent colonization by ETBF is required for tumorigenesis.Methods: We established a method for clearing ETBF in mice, using the antibiotic cefoxitin. Multiple intestinal neoplasia mice were colonized with ETBF for the experiment duration or were cleared of infection after 5 or 14 days. Gross tumors and/or microadenomas were then evaluated. In parallel, IL-17A expression was evaluated in wild-type littermates.Results: Cefoxitin treatment resulted in complete and durable clearance of ETBF colonization. We observed a stepwise increase in median colon tumor numbers as the duration of ETBF colonization increased before cefoxitin treatment. ETBF eradication also significantly decreased mucosal IL-17A expression.Conclusions: The timing of ETBF clearance profoundly influences colon adenoma formation, defining a period during which the colon is susceptible to IL-17A-dependent tumorigenesis in this murine model. This model system can be used to study the microbiota-dependent and molecular mechanisms contributing to IL-17A-dependent colon tumor initiation. [ABSTRACT FROM AUTHOR]

At sites of chronic inflammation, epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation may initiate epigenetic alterations. Previously, we demonstrated that oxidative damage causes epigenetic silencing proteins to become part of a large complex that is localized to GC-rich regions of the genome, including promoter CpG islands that are epigenetically silenced in cancer. However, whether these proteins were recruited directly to damaged DNA or during the DNA repair process was unknown. Here we demonstrate that the mismatch repair protein heterodimer MSH2-MSH6 participates in the oxidative damage-induced recruitment of DNA methyltransferase 1 (DNMT1) to chromatin. Hydrogen peroxide treatment induces the interaction of MSH2-MSH6 with DNMT1, suggesting that the recruitment is through a protein--protein interaction. Importantly, the reduction in transcription for geneswith CpG island-containing promoters caused by oxidative damage is abrogated by knockdown of MSH6 and/or DNMT1. Our findings provide evidence that the role of DNMT1 at sites of oxidative damage is to reduce transcription, potentially preventing transcription from interfering with the repair process. This study uniquely brings together several factors that are known to contribute to colon cancer, namely inflammation, mismatch repair proteins, and epigenetic changes. [ABSTRACT FROM AUTHOR]

Exposures to environmental toxicants and toxins cause epigenetic changes that likely play a role in the development of diseases associated with exposure. The mechanism behind these exposure-induced epigenetic changes is currently unknown. One commonality between most environmental exposures is that they cause DNA damage either directly or through causing an increase in reactive oxygen species, which can damage DNA. Like transcription, DNA damage repair must occur in the context of chromatin requiring both histone modifications and ATP-dependent chromatin remodeling. These chromatin changes aid in DNA damage accessibility and signaling. Several proteins and complexes involved in epigenetic silencing during both development and cancer have been found to be localized to sites of DNA damage. The chromatin-based response to DNA damage is considered a transient event, with chromatin being restored to normal as DNA damage repair is completed. However, in individuals chronically exposed to environmental toxicants or with chronic inflammatory disease, repeated DNA damage-induced chromatin rearrangement may ultimately lead to permanent epigenetic alterations. Understanding the mechanism behind exposure-induced epigenetic changes will allow us to develop strategies to prevent or reverse these changes. This review focuses on epigenetic changes and DNA damage induced by environmental exposures, the chromatin changes that occur around sites of DNA damage, and how these transient chromatin changes may lead to heritable epigenetic alterations at sites of chronic exposure. Environ. Mol. Mutagen. 55:278-291, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The author reflects on the epigenetic changes brought by environmental toxicant exposure to the development of a diverse array of diseases including histone modifications, DNA methylation, and expression of microRNAs. He states the rapid advancement in methodology, technology, and data acquisition made by the field of epigenetics for the identification of multiple genomic loci. An overview on the impact of environmental exposures on the epigenome is offered.

Inflammation plays a role in the initiation and development of many types of cancers, including epithelial ovarian cancer (EOC) and high grade serous ovarian cancer (HGSC), a type of EOC. There are connections between EOC and both peritoneal and ovulation-induced inflammation. Additionally, EOCs have an inflammatory component that contributes to their progression. At sites of inflammation, epithelial cells are exposed to increased levels of inflammatory mediators such as reactive oxygen species, cytokines, prostaglandins, and growth factors that contribute to increased cell division, and genetic and epigenetic changes. These exposure-induced changes promote excessive cell proliferation, increased survival, malignant transformation, and cancer development. Furthermore, the pro-inflammatory tumor microenvironment environment (TME) contributes to EOC metastasis and chemoresistance. In this review we will discuss the roles inflammation and inflammatory mediators play in the development, progression, metastasis, and chemoresistance of EOC. [ABSTRACT FROM AUTHOR]

Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EEC), the neuroendocrine cells of the normal colon epithelium, as compared with non-mCRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. In this study, single-cell multiomics uncovered epigenetic alterations that accompany EEC differentiation, identified STAT3 as a regulator of EEC specification, and discovered a rare cancer-specific cell type with enteric neuron-like characteristics. Furthermore, lysine-specific demethylase 1 (LSD1) and CoREST2 mediated STAT3 demethylation and enhanced STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. Collectively, these results provide a rationale for developing LSD1 inhibitors that target the interaction between LSD1 and STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC. Significance: STAT3 activity mediated by LSD1 and CoREST2 induces enteroendocrine cell specification in mucinous colorectal cancer, suggesting disrupting interaction among LSD1, CoREST2, and STAT3 as a therapeutic strategy to target neuroendocrine differentiation., (©2024 American Association for Cancer Research.)

The persistence of cancer stem cells (CSC) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse in ovarian cancer, the fifth leading cause of cancer-related death among US women. HOXC transcript antisense RNA (HOTAIR) is a long, noncoding RNA (lncRNA) overexpressed in high-grade serous ovarian cancer and linked to chemoresistance. However, HOTAIR impacts chromatin dynamics in ovarian CSCs. Oncogenic lncRNA's contributions to drug-resistant disease are incompletely understood. Here, we generated HOTAIR knockout (KO) high-grade serous ovarian cancer cell lines using paired CRISPR guide RNA design to investigate the function of HOTAIR. We show the loss of HOTAIR function resensitized ovarian cancer cells to platinum treatment and decreased the population of ovarian CSCs. Furthermore, HOTAIR KO inhibited the development of stemness-related phenotypes, including spheroid formation ability and expression of key stemness-associated genes ALDH1A1, NOTCH3, SOX9, and PROM1. HOTAIR KO altered the cellular transcriptome and chromatin accessibility landscape of multiple oncogenic-associated genes and pathways, including the NF-kB pathway. HOTAIR functions as an oncogene by recruiting enhancer of zeste homolog 2 (EZH2) to catalyze H3K27 trimethylation to suppress downstream tumor suppressor genes, and it was of interest to inhibit both HOTAIR and EZH2. In vivo, combining a HOTAIR inhibitor with an EZH2 inhibitor and platinum chemotherapy decreased tumor formation and increased survival. These results suggest a key role for HOTAIR in ovarian CSCs and malignant potential. Targeting HOTAIR in combination with epigenetic therapies may represent a therapeutic strategy to ameliorate ovarian cancer progression and resistance to platinum-based chemotherapy., (©2024 American Association for Cancer Research.)

BRAF activating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis due to an inferior response to standard chemotherapy. Standard of care for patients with refractory metastatic BRAF V600E CRC is treatment with BRAF and EGFR inhibitors. However, responses are not durable. Lineage plasticity to neuroendocrine cancer is an emerging mechanism of targeted therapy resistance in several cancer types. Enteroendocrine cells (EECs), the neuroendocrine cell of the intestine, are uniquely present in BRAF V600E CRC as compared to BRAF wildtype CRC. Here, we demonstrated that combined BRAF and EGFR inhibition enriches for EECs in several models of BRAF V600E CRC. Additionally, EECs and other secretory cell types were enriched in a subset of BRAF V600E CRC patient samples following targeted therapy. Importantly, inhibition of the lysine demethylase LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3., Statement of Significance: Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAF V600E CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs and our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.

Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mucinous CRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics was used to uncover epigenetic alterations that accompany EEC differentiation, identify STAT3 as a novel regulator of EEC specification, and discover a rare cancer-specific cell type with enteric neuron-like characteristics. Further experiments demonstrated that lysine-specific demethylase 1 (LSD1) and CoREST2 mediate STAT3 demethylation and regulate STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. In culmination, these results provide rationale for new LSD1 inhibitors that target the interaction between LSD1 with STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.

Genetic mutations and chronic inflammation of the colon contribute to the development of colorectal cancer (CRC). Using a murine model of inflammation-induced colon tumorigenesis, we determined how genetic mutations alter colon tumor cell differentiation. Inflammation induced by enterotoxigenic Bacteroides fragilis (ETBF) colonization of multiple intestinal neoplasia (Min ApcΔ716/+ ) mice triggers loss of heterozygosity of Apc causing colon tumor formation. Here, we report that the addition of BRAF V600E mutation ( BRAF FV600E Lgr5 tm1(Cre/ERT2)Cle Min ApcΔ716/+ , BLM) or knocking out Msh2 ( Msh2 LoxP/LoxP Vil1-cre Min ApcΔ716/+ , MSH2KO) in the Min model altered colon tumor differentiation. Using single cell RNA-sequencing, we uncovered the differences between BLM, Min, and MSH2KO tumors at a single cell resolution. BLM tumors showed an increase in differentiated tumor epithelial cell lineages and a reduction in the stem cell population. In contrast, MSH2KO tumors were characterized by an increased stem cell population that had higher WNT signaling activity compared to Min tumors. Additionally, comparative analysis of single-cell transcriptomics revealed that BLM tumors had higher expression of transcription factors that drive differentiation, such as Cdx2, than Min tumors. Using RNA velocity, we were able to identify additional potential regulators of BLM tumor differentiation such as NDRG1. The role of CDX2 and NDRG1 as putative regulators for BLM tumor cell differentiation was verified using organoids derived from BLM tumors. Our results demonstrate the critical connections between genetic mutations and cell differentiation in inflammation-induced colon tumorigenesis. Understanding such roles will deepen our understanding of inflammation-associated colon cancer.