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Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription

Oncogene volume 29, pages 5775–5784 (2010)Cite this article

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Abstract

The cytosine analogues 5-azacytidine and 5-aza-2′-deoxycytidine are currently the most advanced drugs for epigenetic cancer therapy. Both drugs function as DNA methyltransferase (DNMT) inhibitors and lead to the reactivation of epigenetically silenced tumour suppressor genes. However, not much is known about their target sequence specificity and their possible side effects on normally methylated sequences such as long interspersed nuclear element (LINE)-1 retroelements. It has been shown that demethylation and activation of the LINE-1 antisense promoter can drive the transcription of neighbouring sequences. In this study, we show that demethylation of the colon carcinoma cell line HCT116, either by treatment with DNMT inhibitors or by genetic disruption of the major DNMTs, induces the expression of an illegitimate fusion transcript between an intronic LINE-1 element and the proto-oncogene cMet (L1-cMet). Similar findings were also obtained with myeloid leukaemia cells, an established cellular model for the approved indication of azacytidine and decitabine. Interestingly, upregulation of L1-cMet transcription resulted in reduced cMet expression, which in turn led to decreased cMet receptor signalling. Our results thus provide an important paradigm for demethylation-dependent modulation of gene expression, even if the promoter of the corresponding gene is unmethylated.

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Acknowledgements

We thank Achim Breiling and Azeemudeen Hussain for their advice and support in chromatin immunoprecipitation and cMet signalling analysis. This work was supported by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and by the Israeli Ministry of Science and Technology (MOST).

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Authors and Affiliations

  1. Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany

    B Weber & F Lyko

  2. Department of Cell & Developmental Biology, Life Sciences Institute, Hebrew University, Jerusalem, Israel

    S Kimhi, G Howard & A Eden

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  1. B Weber
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  2. S Kimhi
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  3. G Howard
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  4. A Eden
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  5. F Lyko
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Correspondence to A Eden or F Lyko.

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Weber, B., Kimhi, S., Howard, G. et al. Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription. Oncogene 29, 5775–5784 (2010). https://doi.org/10.1038/onc.2010.227

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