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Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation

Oncogene volume 32, pages 663–669 (2013)Cite this article

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Abstract

The TET (ten–eleven translocation) family of α-ketoglutarate (α-KG)-dependent dioxygenases catalyzes the sequential oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine, leading to eventual DNA demethylation. The TET2 gene is a bona fide tumor suppressor frequently mutated in leukemia, and TET enzyme activity is inhibited in IDH1/2-mutated tumors by the oncometabolite 2-hydroxyglutarate, an antagonist of α-KG, linking 5mC oxidation to cancer development. We report here that the levels of 5hmC are dramatically reduced in human breast, liver, lung, pancreatic and prostate cancers when compared with the matched surrounding normal tissues. Associated with the 5hmC decrease is the substantial reduction of the expression of all three TET genes, revealing a possible mechanism for the reduced 5hmC in cancer cells. The decrease of 5hmC was also observed during tumor development in different genetically engineered mouse models. Together, our results identify 5hmC as a biomarker whose decrease is broadly and tightly associated with tumor development.

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Acknowledgements

We thank the members of the Fudan MCB laboratory for discussions and support throughout this study, and Eric Oermann for reading the manuscript. This work was supported by MOST 973 (No. 2009CB918401, No. 2011CB910600), NSFC (Grant No. 30600112, 30871255, 31071192). This work was also supported by the 985 Program, Shanghai key project (Grant No. 09JC1402300), the Shanghai Leading Academic Discipline Project (project number B110), and NIH grants (to YX and KLG).

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  1. H Yang and Y Liu: These two authors contributed equally to this work.

Authors and Affiliations

  1. Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China

    H Yang, J-Y Zhang, S-H Ma, D Ye, K-L Guan & Y Xiong

  2. College of Life Science, Fudan University, Shanghai, PR China

    H Yang, S-H Ma & Y Xiong

  3. Department of Pathology, Fudan University, Shanghai, PR China

    Y Liu, J Liu, Z-D Xu & H-G Zhu

  4. Shanghai Medical College, Fudan University, Shanghai, PR China

    Y Liu, J Liu, Z-D Xu, H-G Zhu & K-L Guan

  5. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    F Bai & Y Xiong

  6. Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, PR China

    Z-Q Ling

  7. Department of Pharmacology, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    K-L Guan

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  1. H Yang
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Correspondence to D Ye, K-L Guan or Y Xiong.

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Yang, H., Liu, Y., Bai, F. et al. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 32, 663–669 (2013). https://doi.org/10.1038/onc.2012.67

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  • DOI: https://doi.org/10.1038/onc.2012.67

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