Cargando…

Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation

An in vitro cell transformation assay (CTA) is useful for the detection of non-genotoxic carcinogens (NGTXCs); however, it does not provide information on their modes of action. In this study, to pursue a mechanism-based approach in the risk assessment of NGTXCs, we aimed to develop an integrated st...

Descripción completa

Detalles Bibliográficos
Autores principales: Hwang, Sung-Hee, Yeom, Hojin, Han, Byeal-I, Ham, Byung-Joo, Lee, Yong-Moon, Han, Mi-Ryung, Lee, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432388/
https://www.ncbi.nlm.nih.gov/pubmed/32751172
http://dx.doi.org/10.3390/ijms21155387
_version_ 1783571786507485184
author Hwang, Sung-Hee
Yeom, Hojin
Han, Byeal-I
Ham, Byung-Joo
Lee, Yong-Moon
Han, Mi-Ryung
Lee, Michael
author_facet Hwang, Sung-Hee
Yeom, Hojin
Han, Byeal-I
Ham, Byung-Joo
Lee, Yong-Moon
Han, Mi-Ryung
Lee, Michael
author_sort Hwang, Sung-Hee
collection PubMed
description An in vitro cell transformation assay (CTA) is useful for the detection of non-genotoxic carcinogens (NGTXCs); however, it does not provide information on their modes of action. In this study, to pursue a mechanism-based approach in the risk assessment of NGTXCs, we aimed to develop an integrated strategy comprising an in vitro Bhas 42 CTA and global DNA methylation analysis. For this purpose, 10 NGTXCs, which were also predicted to be negative through Derek/Sarah structure–activity relationship analysis, were first tested for transforming activity in Bhas 42 cells. Methylation profiles using reduced representation bisulfite sequencing were generated for seven NGTXCs that were positive in CTAs. In general, the differentially methylated regions (DMRs) within promoter regions showed slightly more bias toward hypermethylation than the DMRs across the whole genome. We also identified 13 genes associated with overlapping DMRs within the promoter regions in four NGTXCs, of which seven were hypermethylated and six were hypomethylated. Using ingenuity pathway analysis, the genes with DMRs at the CpG sites were found to be enriched in cancer-related categories, including “cell-to-cell signaling and interaction” as well as “cell death and survival”. Moreover, the networks related to “cell death and survival”, which were considered to be associated with carcinogenesis, were identified in six NGTXCs. These results suggest that epigenetic changes supporting cell transformation processes occur during non-genotoxic carcinogenesis. Taken together, our combined system can become an attractive component for an integrated approach for the testing and assessment of NGTXCs.
format Online
Article
Text
id pubmed-7432388
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-74323882020-08-24 Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation Hwang, Sung-Hee Yeom, Hojin Han, Byeal-I Ham, Byung-Joo Lee, Yong-Moon Han, Mi-Ryung Lee, Michael Int J Mol Sci Article An in vitro cell transformation assay (CTA) is useful for the detection of non-genotoxic carcinogens (NGTXCs); however, it does not provide information on their modes of action. In this study, to pursue a mechanism-based approach in the risk assessment of NGTXCs, we aimed to develop an integrated strategy comprising an in vitro Bhas 42 CTA and global DNA methylation analysis. For this purpose, 10 NGTXCs, which were also predicted to be negative through Derek/Sarah structure–activity relationship analysis, were first tested for transforming activity in Bhas 42 cells. Methylation profiles using reduced representation bisulfite sequencing were generated for seven NGTXCs that were positive in CTAs. In general, the differentially methylated regions (DMRs) within promoter regions showed slightly more bias toward hypermethylation than the DMRs across the whole genome. We also identified 13 genes associated with overlapping DMRs within the promoter regions in four NGTXCs, of which seven were hypermethylated and six were hypomethylated. Using ingenuity pathway analysis, the genes with DMRs at the CpG sites were found to be enriched in cancer-related categories, including “cell-to-cell signaling and interaction” as well as “cell death and survival”. Moreover, the networks related to “cell death and survival”, which were considered to be associated with carcinogenesis, were identified in six NGTXCs. These results suggest that epigenetic changes supporting cell transformation processes occur during non-genotoxic carcinogenesis. Taken together, our combined system can become an attractive component for an integrated approach for the testing and assessment of NGTXCs. MDPI 2020-07-29 /pmc/articles/PMC7432388/ /pubmed/32751172 http://dx.doi.org/10.3390/ijms21155387 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hwang, Sung-Hee
Yeom, Hojin
Han, Byeal-I
Ham, Byung-Joo
Lee, Yong-Moon
Han, Mi-Ryung
Lee, Michael
Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation
title Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation
title_full Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation
title_fullStr Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation
title_full_unstemmed Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation
title_short Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation
title_sort predicting carcinogenic mechanisms of non-genotoxic carcinogens via combined analysis of global dna methylation and in vitro cell transformation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432388/
https://www.ncbi.nlm.nih.gov/pubmed/32751172
http://dx.doi.org/10.3390/ijms21155387
work_keys_str_mv AT hwangsunghee predictingcarcinogenicmechanismsofnongenotoxiccarcinogensviacombinedanalysisofglobaldnamethylationandinvitrocelltransformation
AT yeomhojin predictingcarcinogenicmechanismsofnongenotoxiccarcinogensviacombinedanalysisofglobaldnamethylationandinvitrocelltransformation
AT hanbyeali predictingcarcinogenicmechanismsofnongenotoxiccarcinogensviacombinedanalysisofglobaldnamethylationandinvitrocelltransformation
AT hambyungjoo predictingcarcinogenicmechanismsofnongenotoxiccarcinogensviacombinedanalysisofglobaldnamethylationandinvitrocelltransformation
AT leeyongmoon predictingcarcinogenicmechanismsofnongenotoxiccarcinogensviacombinedanalysisofglobaldnamethylationandinvitrocelltransformation
AT hanmiryung predictingcarcinogenicmechanismsofnongenotoxiccarcinogensviacombinedanalysisofglobaldnamethylationandinvitrocelltransformation
AT leemichael predictingcarcinogenicmechanismsofnongenotoxiccarcinogensviacombinedanalysisofglobaldnamethylationandinvitrocelltransformation