The epigenetics of tumour initiation: cancer stem cells and their chromatin

Avgustinova, Alexandra; Benitah, Salvador Aznar

doi:10.1016/j.gde.2016.01.003

Cited by 54 publications

(52 citation statements)

References 76 publications

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“…Epigenetic states required for stemness place chromatin in a state that allows for transcription widely across genes while simultaneously allowing for suppression of genes involved in differentiation. The role of epigenetic modifiers in normal and cancer stem cell (CSC) maintenance has been reviewed . In ACC, the histone 3 lysine 27 demethylase (KDM6A) is recurrently the target of splice and frameshift mutations, with the mutation rate ranging from 7% in mixed‐grade ACC to 18% in high‐grade ACC .…”

Section: Resultsmentioning

confidence: 99%

Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

Yarbrough

Panaccione

Chang

et al. 2016

Laryngoscope Investig Oto

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ObjectivesThis review surveys trialed therapies and molecular defects in adenoid cystic carcinoma (ACC), with an emphasis on neural crest‐like stemness characteristics of newly discovered cancer stem cells (CSCs) and therapies that may target these CSCs.Data SourcesArticles available on Pubmed or OVID MEDLINE databases and unpublished data.Review MethodsSystematic review of articles pertaining to ACC and neural crest‐like stem cells.ResultsAdenoid cystic carcinoma of the salivary gland is a slowly growing but relentless cancer that is prone to nerve invasion and metastases. A lack of understanding of molecular etiology and absence of targetable drivers has limited therapy for patients with ACC to surgery and radiation. Currently, no curative treatments are available for patients with metastatic disease, which highlights the need for effective new therapies. Research in this area has been inhibited by the lack of validated cell lines and a paucity of clinically useful markers. The ACC research environment has recently improved, thanks to the introduction of novel tools, technologies, approaches, and models. Improved understanding of ACC suggests that neural crest‐like stemness is a major target in this rare tumor. New cell culture techniques and patient‐derived xenografts provide tools for preclinical testing.ConclusionPreclinical research has not identified effective targets in ACC, as confirmed by the large number of failed clinical trials. New molecular data suggest that drivers of neural crest‐like stemness may be required for maintenance of ACC; as such, CSCs are a target for therapy of ACC.

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Section: Resultsmentioning

confidence: 99%

Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

Yarbrough

Panaccione

Chang

et al. 2016

Laryngoscope Investig Oto

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“…In several studies, KDM5A/B and KDM6A/B activity was required to produce a slow‐cycling, drug‐resistant phenotype in a broad spectrum of malignancies . Other chromatin modifiers play similar roles; for example, EZH2 (H3K27 methylase) was shown to promote epithelial–mesenchymal transition (EMT), a cancer stem‐like program that promotes cancer initiation and metastasis …”

Section: Introductionmentioning

confidence: 99%

Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype

Wei

et al. 2020

Intl Journal of Cancer

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Highly tumorigenic, drug‐resistant cancer stem‐like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem‐like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem‐like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem‐like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug‐resistant phenotype.

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“…Histone modification plays important roles in various cellular functions and cancer; they affect gene expression by changing the state of transcription factors accessing to chromatin . The post‐translational modification of histone tails also affects different levels of DNA organization, including acetylation, phosphorylation, methylation, ubiquitylation, and ADP ribosylation on it amino acid residues, the combination of these modifications are important marks of epigenetics, commonly known as “histone code.” Increasing evidences have indicated its role in tumor initiation and development …”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori infection‐induced H3Ser10 phosphorylation in stepwise gastric carcinogenesis and its clinical implications

et al. 2018

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BackgroundOur previous works have demonstrated that Helicobacter pylori (Hp) infection can alter histone H3 serine 10 phosphorylation status in gastric epithelial cells. However, whether Helicobacter pylori‐induced histone H3 serine 10 phosphorylation participates in gastric carcinogenesis is unknown. We investigate the expression of histone H3 serine 10 phosphorylation in various stages of gastric disease and explore its clinical implication.Materials and MethodsStomach biopsy samples from 129 patients were collected and stained with histone H3 serine 10 phosphorylation, Ki67, and Helicobacter pylori by immunohistochemistry staining, expressed as labeling index. They were categorized into nonatrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, low‐grade intraepithelial neoplasia, high‐grade intraepithelial neoplasia, and intestinal‐type gastric cancer groups. Helicobacter pylori infection was determined by either 13C‐urea breath test or immunohistochemistry staining.ResultsIn Helicobacter pylori‐negative patients, labeling index of histone H3 serine 10 phosphorylation was gradually increased in nonatrophic gastritis, chronic atrophic gastritis, intestinal metaplasia groups, peaked at low‐grade intraepithelial neoplasia, and declined in high‐grade intraepithelial neoplasia and gastric cancer groups. In Helicobacter pylori‐infected patients, labeling index of histone H3 serine 10 phosphorylation followed the similar pattern as above, with increased expression over the corresponding Helicobacter pylori‐negative controls except in nonatrophic gastritis patient whose labeling index was decreased when compared with Helicobacter pylori‐negative control. Labeling index of Ki67 in Helicobacter pylori‐negative groups was higher in gastric cancer than chronic atrophic gastritis and low‐grade intraepithelial neoplasia groups, and higher in intestinal metaplasia group compared with chronic atrophic gastritis group. In Helicobacter pylori‐positive groups, Ki67 labeling index was increased stepwise from nonatrophic gastritis to gastric cancer except slightly decrease in chronic atrophic gastritis group. In addition, we noted that histone H3 serine 10 phosphorylation staining is accompanied with its location changes from gastric gland bottom expanded to whole gland as disease stage progress.ConclusionsThese results indicate that stepwise gastric carcinogenesis is associated with altered histone H3 serine 10 phosphorylation, Helicobacter pylori infection enhances histone H3 serine 10 phosphorylation expression in these processes; it is also accompanied with histone H3 serine 10 phosphorylation location change from gland bottom staining expand to whole gland expression. The results suggest that epigenetic dysregulation may play important roles in Helicobacter pylori‐induced gastric cancer.

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The epigenetics of tumour initiation: cancer stem cells and their chromatin

Cited by 54 publications

References 76 publications

Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype

Helicobacter pylori infection‐induced H3Ser10 phosphorylation in stepwise gastric carcinogenesis and its clinical implications

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