Competition between DNA methylation, nucleotide synthesis, and antioxidation in cancer versus normal tissues

Sha Cao, Xiwen Zhu, Chi Zhang, Hong Qian, Heinz Bernd Schuttler, Jianping Gong, Ying Xu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Global DNA hypomethylation occurs in many cancer types, but there is no explanation for its differential occurrence or possible impact on cancer cell physiology. Here we address these issues with a computational study of genome-scale DNA methylation in 16 cancer types. Specifically, we identified (i) a possible determinant for global DNA methylation in cancer cells and (ii) a relationship between levels of DNA methylation, nucleotide synthesis, and intracellular oxidative stress in cells. We developed a system of kinetic equations to capture the metabolic relations among DNA methylation, nucleotide synthesis, and antioxidative stress response, including their competitions for methyl and sulfur groups, based on known information about one-carbon metabolism and trans-sulfuration pathways. We observed a kinetic-based regulatory mechanism that controls reaction rates of the three competing processes when their shared resources are limited, particularly when the nucleotide synthesis rates or oxidative states are high. The combination of this regulatory mechanism and the need for rapid nucleotide synthesis, as well as high production of glutathione dictated by cancer-driving forces, led to the nearly universal observations of reduced global DNA methylation in cancer. Our model provides a natural explanation for differential global DNA methylation levels across cancer types and supports the observation that more malignant cancers tend to exhibit reduced DNA methylation levels. Insights obtained from this work provide useful information about the complexities of cancer due to interplays among competing, dynamic biological processes.

Original languageEnglish (US)
Pages (from-to)4185-4195
Number of pages11
JournalCancer Research
Volume77
Issue number15
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

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DNA Methylation
Nucleotides
Neoplasms
Biological Phenomena
Cell Physiological Phenomena
Sulfur
Glutathione
Oxidative Stress
Carbon
Genome
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Competition between DNA methylation, nucleotide synthesis, and antioxidation in cancer versus normal tissues. / Cao, Sha; Zhu, Xiwen; Zhang, Chi; Qian, Hong; Schuttler, Heinz Bernd; Gong, Jianping; Xu, Ying.

In: Cancer Research, Vol. 77, No. 15, 01.08.2017, p. 4185-4195.

Research output: Contribution to journalArticle

Cao, Sha ; Zhu, Xiwen ; Zhang, Chi ; Qian, Hong ; Schuttler, Heinz Bernd ; Gong, Jianping ; Xu, Ying. / Competition between DNA methylation, nucleotide synthesis, and antioxidation in cancer versus normal tissues. In: Cancer Research. 2017 ; Vol. 77, No. 15. pp. 4185-4195.
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