Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma

Wenjing Wu, Tushar D. Bhagat, Xue Yang, Jee Hoon Song, Yulan Cheng, Rachana Agarwal, John M. Abraham, Sariat Ibrahim, Matthias Bartenstein, Zulfiqar Hussain, Masako Suzuki, Yiting Yu, Wei Chen, Charis Eng, John M. Greally, Amit K. Verma, Stephen J. Meltzer

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Background & Aims: Alterations in methylation of protein-coding genes are associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Dysregulation of noncoding RNAs occurs during carcinogenesis but has never been studied in BE or EAC. We applied high-resolution methylome analysis to identify changes at genomic regions that encode noncoding RNAs in BE and EAC. Methods: We analyzed methylation of 1.8 million CpG sites using massively parallel sequencing-based HELP tagging in matched EAC, BE, and normal esophageal tissues. We also analyzed human EAC (OE33, SKGT4, and FLO-1) and normal (HEEpic) esophageal cells. Results: BE and EAC exhibited genome-wide hypomethylation, significantly affecting intragenic and repetitive genomic elements as well as noncoding regions. These methylation changes targeted small and long noncoding regions, discriminating normal from matched BE or EAC tissues. One long noncoding RNA, AFAP1-AS1, was extremely hypomethylated and overexpressed in BE and EAC tissues and EAC cells. Its silencing by small interfering RNA inhibited proliferation and colony-forming ability, induced apoptosis, and reduced EAC cell migration and invasion without altering the expression of its protein-coding counterpart, AFAP1. Conclusions: BE and EAC exhibit reduced methylation that includes noncoding regions. Methylation of the long noncoding RNA AFAP1-AS1 is reduced in BE and EAC, and its expression inhibits cancer-related biologic functions of EAC cells.

Original languageEnglish (US)
JournalGastroenterology
Volume144
Issue number5
DOIs
StatePublished - May 2013

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Long Noncoding RNA
Barrett Esophagus
Adenocarcinoma
DNA
Methylation
Untranslated RNA
High-Throughput Nucleotide Sequencing
Small Interfering RNA
Cell Movement

Keywords

  • Esophageal Cancer Progression
  • Gene Regulation
  • Noncoding RNA
  • Tumor Development

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma. / Wu, Wenjing; Bhagat, Tushar D.; Yang, Xue; Song, Jee Hoon; Cheng, Yulan; Agarwal, Rachana; Abraham, John M.; Ibrahim, Sariat; Bartenstein, Matthias; Hussain, Zulfiqar; Suzuki, Masako; Yu, Yiting; Chen, Wei; Eng, Charis; Greally, John M.; Verma, Amit K.; Meltzer, Stephen J.

In: Gastroenterology, Vol. 144, No. 5, 05.2013.

Research output: Contribution to journalArticle

Wu, W, Bhagat, TD, Yang, X, Song, JH, Cheng, Y, Agarwal, R, Abraham, JM, Ibrahim, S, Bartenstein, M, Hussain, Z, Suzuki, M, Yu, Y, Chen, W, Eng, C, Greally, JM, Verma, AK & Meltzer, SJ 2013, 'Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma', Gastroenterology, vol. 144, no. 5. https://doi.org/10.1053/j.gastro.2013.01.019
Wu, Wenjing ; Bhagat, Tushar D. ; Yang, Xue ; Song, Jee Hoon ; Cheng, Yulan ; Agarwal, Rachana ; Abraham, John M. ; Ibrahim, Sariat ; Bartenstein, Matthias ; Hussain, Zulfiqar ; Suzuki, Masako ; Yu, Yiting ; Chen, Wei ; Eng, Charis ; Greally, John M. ; Verma, Amit K. ; Meltzer, Stephen J. / Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma. In: Gastroenterology. 2013 ; Vol. 144, No. 5.
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abstract = "Background & Aims: Alterations in methylation of protein-coding genes are associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Dysregulation of noncoding RNAs occurs during carcinogenesis but has never been studied in BE or EAC. We applied high-resolution methylome analysis to identify changes at genomic regions that encode noncoding RNAs in BE and EAC. Methods: We analyzed methylation of 1.8 million CpG sites using massively parallel sequencing-based HELP tagging in matched EAC, BE, and normal esophageal tissues. We also analyzed human EAC (OE33, SKGT4, and FLO-1) and normal (HEEpic) esophageal cells. Results: BE and EAC exhibited genome-wide hypomethylation, significantly affecting intragenic and repetitive genomic elements as well as noncoding regions. These methylation changes targeted small and long noncoding regions, discriminating normal from matched BE or EAC tissues. One long noncoding RNA, AFAP1-AS1, was extremely hypomethylated and overexpressed in BE and EAC tissues and EAC cells. Its silencing by small interfering RNA inhibited proliferation and colony-forming ability, induced apoptosis, and reduced EAC cell migration and invasion without altering the expression of its protein-coding counterpart, AFAP1. Conclusions: BE and EAC exhibit reduced methylation that includes noncoding regions. Methylation of the long noncoding RNA AFAP1-AS1 is reduced in BE and EAC, and its expression inhibits cancer-related biologic functions of EAC cells.",
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T1 - Hypomethylation of noncoding DNA regions and overexpression of the long noncoding RNA, AFAP1-AS1, in Barrett's esophagus and esophageal adenocarcinoma

AU - Wu, Wenjing

AU - Bhagat, Tushar D.

AU - Yang, Xue

AU - Song, Jee Hoon

AU - Cheng, Yulan

AU - Agarwal, Rachana

AU - Abraham, John M.

AU - Ibrahim, Sariat

AU - Bartenstein, Matthias

AU - Hussain, Zulfiqar

AU - Suzuki, Masako

AU - Yu, Yiting

AU - Chen, Wei

AU - Eng, Charis

AU - Greally, John M.

AU - Verma, Amit K.

AU - Meltzer, Stephen J.

PY - 2013/5

Y1 - 2013/5

N2 - Background & Aims: Alterations in methylation of protein-coding genes are associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Dysregulation of noncoding RNAs occurs during carcinogenesis but has never been studied in BE or EAC. We applied high-resolution methylome analysis to identify changes at genomic regions that encode noncoding RNAs in BE and EAC. Methods: We analyzed methylation of 1.8 million CpG sites using massively parallel sequencing-based HELP tagging in matched EAC, BE, and normal esophageal tissues. We also analyzed human EAC (OE33, SKGT4, and FLO-1) and normal (HEEpic) esophageal cells. Results: BE and EAC exhibited genome-wide hypomethylation, significantly affecting intragenic and repetitive genomic elements as well as noncoding regions. These methylation changes targeted small and long noncoding regions, discriminating normal from matched BE or EAC tissues. One long noncoding RNA, AFAP1-AS1, was extremely hypomethylated and overexpressed in BE and EAC tissues and EAC cells. Its silencing by small interfering RNA inhibited proliferation and colony-forming ability, induced apoptosis, and reduced EAC cell migration and invasion without altering the expression of its protein-coding counterpart, AFAP1. Conclusions: BE and EAC exhibit reduced methylation that includes noncoding regions. Methylation of the long noncoding RNA AFAP1-AS1 is reduced in BE and EAC, and its expression inhibits cancer-related biologic functions of EAC cells.

AB - Background & Aims: Alterations in methylation of protein-coding genes are associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Dysregulation of noncoding RNAs occurs during carcinogenesis but has never been studied in BE or EAC. We applied high-resolution methylome analysis to identify changes at genomic regions that encode noncoding RNAs in BE and EAC. Methods: We analyzed methylation of 1.8 million CpG sites using massively parallel sequencing-based HELP tagging in matched EAC, BE, and normal esophageal tissues. We also analyzed human EAC (OE33, SKGT4, and FLO-1) and normal (HEEpic) esophageal cells. Results: BE and EAC exhibited genome-wide hypomethylation, significantly affecting intragenic and repetitive genomic elements as well as noncoding regions. These methylation changes targeted small and long noncoding regions, discriminating normal from matched BE or EAC tissues. One long noncoding RNA, AFAP1-AS1, was extremely hypomethylated and overexpressed in BE and EAC tissues and EAC cells. Its silencing by small interfering RNA inhibited proliferation and colony-forming ability, induced apoptosis, and reduced EAC cell migration and invasion without altering the expression of its protein-coding counterpart, AFAP1. Conclusions: BE and EAC exhibit reduced methylation that includes noncoding regions. Methylation of the long noncoding RNA AFAP1-AS1 is reduced in BE and EAC, and its expression inhibits cancer-related biologic functions of EAC cells.

KW - Esophageal Cancer Progression

KW - Gene Regulation

KW - Noncoding RNA

KW - Tumor Development

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