Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

Eckstein, Meredith; Eleazer, Rebekah; Rea, Matthew; Fondufe‐Mittendorf, Yvonne

doi:10.1515/reveh-2016-0025

Cited by 35 publications

(25 citation statements)

References 150 publications

(181 reference statements)

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“…Evidence suggests that ROS react with DNA and induce structural DNA damage leading to genetic defects. Moreover, overexpression of antioxidant enzymes in response to As-induced oxidative stress will desensitize cells to apoptosis, which allows cancer cells to persist instead of die (43; 44). Of note, arsenic can cause oxidative stress either through direct Fenton-type reactions to produce ROS, or indirect depletion of important antioxidants such as glutathione (45-47).…”

Section: Introductionmentioning

confidence: 99%

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Metals and Mechanisms of Carcinogenesis

Chen

DesMarais

Costa

2019

Annu. Rev. Pharmacol. Toxicol.

210

106

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Metal exposure is pervasive and not limited to sporadic poisoning events or toxic waste sites. Hundreds of millions of people around the globe are affected by chronic metal exposure, which is associated with serious health concerns including cancer, as demonstrated in a variety of studies at the molecular, systemic, and epidemiologic levels. Metal-induced toxicity and carcinogenicity is sophisticated and complex in nature. This review provides a broad context and holistic view of currently available studies on the mechanisms of metal-induced carcinogenesis. Specifically, we focus on the five most prevailing carcinogenic metals: arsenic, nickel, cadmium, chromium, and beryllium, and their potential to drive carcinogenesis in humans. A comprehensive understanding of the mechanisms behind the development of metal-induced cancer can provide valuable insights for potential cancer therapeutics.

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Section: Introductionmentioning

confidence: 99%

“…Epigenetic alterations including changes in DNA methylation, histone PTMs, and miRNA expression can hinder chromatin accessibility to regulatory factors and thereby affect gene expression at transcription initiation and gene splicing. (43). As-induced global epigenetic alterations were first discovered in the 1980s (51).…”

Section: Introductionmentioning

confidence: 99%

Metals and Mechanisms of Carcinogenesis

Chen

DesMarais

Costa

2019

Annu. Rev. Pharmacol. Toxicol.

210

106

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“…It is generally accepted that epigenetic mechanism may play a key role in arenic-induced tumorigenesis mostly due to its weakly genotoxic carcinogen 22,23 . Recent findings revealed that noncoding RNAs, especially of microRNAs, have participated in arsenic-induced cellular transformation and tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Malignant Transformation of Human Bronchial Epithelial Cells Induced by Arsenic through STAT3/miR-301a/SMAD4 Loop

Zhong

Huang

Wang

et al. 2018

Sci Rep

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Arsenic is a well-known of human carcinogen and miR-301a is an oncogenic microRNA, which links to oncogenesis, however, little is understood about its contribution to arsenic-induced cellular transformation and tumorigenesis. Here, we investigated the role of miR-301a during arsenic-induced cellular transformation and tumor formation. miR-301a was found to be upregulated during arsenic-induced BEAS-2B transformation and the overexpression of miR-301a was dependent on IL-6/STAT3 signaling. Inhibition of miR-301a leads to reduction of cell proliferation, colony formation and cell migration. By using dual luciferase assay, SMAD4 was confirmed to be a direct target of miR-301a in BEAS-2B cells and upregulation of SMAD4 is involved the restraining cell growth and migration. In addition, reducing of miR-301a expression enhances doxorubicin-induced cellular apoptosis of transformed BEAS-2B through up-regulating SMAD4. Furthermore, we demonstrated that downregulation of miR-301a in BEAS-2B attenuates tumor growth in the xenograft model by targeting SMAD4. Of note, the level of miR-301a expression correlated inversely with SMAD4 expression in clinical specimens of human lung cancer. Our findings ascertain that miR-301a is an oncogenic miRNA, which targets SMAD4 to establish an essential mechanism for arsenic-induced carcinogenesis, IL-6/STAT3/miR-301a/SMAD4 signaling pathways.

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“…One more reasonable assumption is that exposure at high doses and low doses highly likely shares similar epigenetic mechanism. To our goal, we choose 0, 2, 5, and 10 μ M sodium arsenite based on published papers (Shi et al, 2004;Chervona et al, 2012a;Wang et al, 2013;Eckstein et al, 2017) for treatment.…”

Section: Discussionmentioning

confidence: 99%

Arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in low-dose exposed mouse embryonic fibroblast cells

Zhu

Lou

et al. 2018

Preprint

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Epidemiological investigations have validated the positive relationships between arsenic in drinking water and several cancers, including skin, liver and lung cancers. Besides genotoxicity, arsenic exposure-related pathogenesis of disease is widely considered through epigenetic mechanisms; however, the underlying mechanistic insight remains elusive. Herein we explore the initial epigenetic changes via acute low-dose arsenite exposures of mouse embryonic fibroblast (MEF) cells and Dot1L knockout MEF (Dot1L-/-for abbreviation) cells. Our RNA-seq and Western blot data demonstrated that, in both cell lines, acute low-dose arsenite exposure abolished histone acetyltransferase p300 at the RNA level and subsequent protein level. Consequently, p300-specific main target histone H3K27ac, a marker separating active from poised enhancers, decreased dramatically as validated by both Western blot and ChIP-seq analyses. Concomitantly, H3K4me1 as another well-known marker for enhancers also showed significant decreases, suggesting an underappreciated crosstalk between H3K4me1 and H3K27ac involved in arsenite exposure. Significantly, arsenite exposure-reduced H3K27ac and H3K4me1 inhibit the expression of genes including EP300 itself and Kruppel Like Factor 4(Klf4), a tumor suppressor gene. Collectively, our investigations identify p300 as an internal bridging factor within cells to sense external environmental arsenite exposure to alter chromatin, thereby changing gene transcription for disease pathogenesis.

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Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

Cited by 35 publications

References 150 publications

Metals and Mechanisms of Carcinogenesis

Metals and Mechanisms of Carcinogenesis

Malignant Transformation of Human Bronchial Epithelial Cells Induced by Arsenic through STAT3/miR-301a/SMAD4 Loop

Arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in low-dose exposed mouse embryonic fibroblast cells

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