Computational trans-omics approach characterised methylomic and transcriptomic involvements and identified novel therapeutic targets for chemoresistance in gastrointestinal cancer stem cells

Masamitsu Konno, Hidetoshi Matsui, Jun Koseki, Ayumu Asai, Yoshihiro Kano, Koichi Kawamoto, Naohiro Nishida, Daisuke Sakai, Toshihiro Kudo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii

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Abstract

We investigated the relationship between methylomic [5-methylation on deoxycytosine to form 5-methylcytosine (5mC)] and transcriptomic information in response to chemotherapeutic 5-fluorouracil (5-FU) exposure and cisplatin (CDDP) administration using the ornithine decarboxylase (ODC) degron-positive cancer stem cell model of gastrointestinal tumour. The quantification of 5mC methylation revealed various alterations in the size distribution and intensity of genomic loci for each patient. To summarise these alterations, we transformed all large volume data into a smooth function and treated the area as a representative value of 5mC methylation. The present computational approach made the methylomic data more accessible to each transcriptional unit and allowed to identify candidate genes, including the tumour necrosis factor receptor-associated factor 4 (TRAF4), as novel therapeutic targets with a strong response to anti-tumour agents, such as 5-FU and CDDP, and whose significance has been confirmed in a mouse model in vivo. The present study showed that 5mC methylation levels are inversely correlated with gene expression in a chemotherapy-resistant stem cell model of gastrointestinal cancer. This mathematical method can be used to simultaneously quantify and identify chemoresistant potential targets in gastrointestinal cancer stem cells.

Original languageEnglish
Article number899
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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5-Methylcytosine
Gastrointestinal Neoplasms
Neoplastic Stem Cells
Methylation
Fluorouracil
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Ornithine Decarboxylase
Therapeutics
Cisplatin
Neoplasms
Stem Cells
Gene Expression
Drug Therapy
Genes

All Science Journal Classification (ASJC) codes

  • General

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Computational trans-omics approach characterised methylomic and transcriptomic involvements and identified novel therapeutic targets for chemoresistance in gastrointestinal cancer stem cells. / Konno, Masamitsu; Matsui, Hidetoshi; Koseki, Jun; Asai, Ayumu; Kano, Yoshihiro; Kawamoto, Koichi; Nishida, Naohiro; Sakai, Daisuke; Kudo, Toshihiro; Satoh, Taroh; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi.

In: Scientific reports, Vol. 8, No. 1, 899, 01.12.2018.

Research output: Contribution to journalArticle

Konno, Masamitsu ; Matsui, Hidetoshi ; Koseki, Jun ; Asai, Ayumu ; Kano, Yoshihiro ; Kawamoto, Koichi ; Nishida, Naohiro ; Sakai, Daisuke ; Kudo, Toshihiro ; Satoh, Taroh ; Doki, Yuichiro ; Mori, Masaki ; Ishii, Hideshi. / Computational trans-omics approach characterised methylomic and transcriptomic involvements and identified novel therapeutic targets for chemoresistance in gastrointestinal cancer stem cells. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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