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TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway

Oncogene volume 34, pages 4168–4176 (2015)Cite this article

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Abstract

Ten eleven translocation (TET) enzymes catalyse the oxidative reactions of 5-methylcytosine (5mC) to promote the demethylation process. The reaction intermediate 5-hydroxymethylcytosine (5hmC) has been shown to be abundant in embryonic stem cells and tissues but strongly depleted in human cancers. Genetic mutations of TET2 gene were associated with leukaemia, whereas TET1 downregulation has been shown to promote malignancy in breast cancer. Here we report that TET1 is downregulated in colon tumours from the initial stage. TET1 silencing in primary epithelial colon cells increase their cellular proliferation while its re-expression in colon cancer cells inhibits their proliferation and the growth of tumour xenografts even at later stages. We found that TET1 binds to the promoter of the DKK gene inhibitors of the WNT signalling to maintain them hypomethylated. Downregulation of TET1 during colon cancer initiation leads to repression, by DNA methylation, the promoters of the inhibitors of the WNT pathway resulting in a constitutive activation of the WNT pathway. Thus the DNA hydroxymethylation mediated by TET1 controlling the WNT signalling is a key player of tumour growth. These results provide new insights for understanding how tumours escape cellular controls.

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Acknowledgements

This work was supported by the Associazione Italiana Ricerca sul Cancro (AIRC) IG 2011/11982. We thank Carola Ponzetto and Riccardo Taulli for the critical reading of the manuscript.

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Authors and Affiliations

  1. Epigenetics, Human Genetics Foundation (HuGeF), Torino, Italy

    F Neri, D Dettori, D Incarnato, A Krepelova, S Rapelli, M Maldotti, C Parlato & S Oliviero

  2. Dipartimento di Biotecnologie Chimica e Farmacia, Università di Siena, Siena, Italy

    D Incarnato, A Krepelova & S Rapelli

  3. Dipartimento di Scienze Chirurgiche, Microchirurgiche e Mediche, Università di Sassari, Sassari, Italy

    P Paliogiannis

  4. Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino, Torino, Italy

    S Oliviero

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Correspondence to S Oliviero.

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Neri, F., Dettori, D., Incarnato, D. et al. TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway. Oncogene 34, 4168–4176 (2015). https://doi.org/10.1038/onc.2014.356

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