Hypomethylation reduced the aggressive potential of human malignant mesothelioma cells

Our plain-English summary of Hypomethylation reduced the aggressive potential of human malignant mesothelioma cells, by N.Y. Kim, M.C. Kim, Y. Kim (Cancer Gene Therapy, 2016).

The study

• Authors: N.Y. Kim, M.C. Kim, Y. Kim
• Journal: Cancer Gene Therapy
• Published: 2016;23(12):425-432
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Epigenetic modifications have been implicated in the development of therapeutic resistance responsible for the poor prognosis of human malignant mesothelioma (HMM). To find a potential way to overcome this therapeutic resistance, this study investigated the anticancer effects of a DNA demethylating agent, 5-Aza-2'-Deoxycytidine (5-aza-dC), on HMM cells. The 5-aza-dC exhibited minimal detrimental effects on cell survival. However, treatment with 5-aza-dC significantly altered the biological characteristics associated with malignancy, such as cell migration and cell interaction, colony-forming capacity, and invasiveness. Moreover, it significantly reduced the fraction of side population (SP) cells, which are reportedly enriched for more aggressive cells. Large-scale methylation analysis based on methylated DNA immunoprecipitation revealed a more than two fold increase in the methylation level of major tumor suppressor genes in the SP fraction. The data indicated that SP cells might acquire malignancy by hypermethylation of tumor suppressor genes. Treatment with 5-aza-dC could attack more malignant cells through the modification of their methylation status. The results indicate that the modulation of DNA methylation might be a valuable strategy to overcome the therapeutic resistance of HMM. Moreover, ensuing changes in the biological characteristics provide a basis for further analysis of the role of methylation in HMM carcinogenesis.

In plain English

This was a laboratory study of two human malignant mesothelioma cell lines, MS1 and NCI-H513 (H513), grown in culture. It did not involve patients or asbestos exposure. The authors treated the cells with 5-aza-2′-deoxycytidine (5-aza-dC), a drug that removes chemical methyl tags from DNA, at 10 or 20 micromolar. The drug did not significantly change cell survival. Changes in the share of dying (apoptotic) cells were not statistically significant: from 1.7 to 1.8% in MS1 cells and from 2.1 to 1.8% in H513 cells. Treatment significantly reduced the number of colonies the cells formed, their migration, and their invasion through a gel barrier. It also lowered the share of side population cells, a subgroup described as more aggressive, from 0.9 to 0.2% in MS1 cells and from 0.7 to 0.5% in H513 cells. Major tumor suppressor genes showed more than twofold higher methylation in side population cells than in other cells. The authors concluded that 5-aza-dC is a cytostatic agent in mesothelioma, meaning it holds back cell growth rather than killing cells, with potential implications for overcoming chemoresistance. They said how the drug reduced invasiveness needs further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) experiment on human malignant mesothelioma cell lines treated with a DNA demethylating drug
• Who was studied: two human malignant mesothelioma cell lines, NCI-H513 (H513) and MS1, grown in culture; no patients were studied
• Exposure: the DNA demethylating drug 5-aza-2′-deoxycytidine (5-aza-dC) at 10 or 20 micromolar; no asbestos or other fiber exposure was studied
• Main results:
  • 5-aza-dC did not significantly change cell viability compared with untreated control cells
  • Apoptotic cells rose from 1.7 to 1.8% in MS1 cells and fell from 2.1 to 1.8% in H513 cells; neither change was statistically significant
  • The total number of colonies formed by the mesothelioma cells was significantly decreased by 5-aza-dC treatment
  • Both 10 and 20 micromolar 5-aza-dC significantly decreased the number of migrating mesothelioma cells in a scratch-wound assay after 24 hours
  • Invasion through a Matrigel-coated filter was significantly reduced in treated MS1 cells (p less than 0.05) and H513 cells (p less than 0.001)
  • The percentage of side population cells fell from 0.9 to 0.2% in MS1 cells and from 0.7 to 0.5% in H513 cells after treatment
  • Major tumor suppressor genes showed a greater than twofold increase in methylation in side population cells compared with non-side population cells
  • 5-aza-dC lowered DNMT3B mRNA levels and DNMT3A protein levels
  • 5-aza-dC did not change expression of the tumor suppressor genes p53, RASFF1A and RARβ
• The authors' conclusion: The authors concluded that 5-aza-dC is a cytostatic agent in mesothelioma with potential implications for a therapeutic measure to overcome chemoresistance
• Limitations the authors state:
  • The authors stated that the mechanism by which 5-aza-dC suppressed invasiveness needs further study
  • The authors noted that the unchanged expression of tumor suppressor genes appeared to contradict the proposal that 5-aza-dC works by restoring those genes

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Prognosis, Tumor Suppressor Gene, Carcinogenesis.

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• Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine — D. Roulois, S. Deshayes, et al. (2016)
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