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

Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
Oncogene (Impact Factor: 8.56). 10/2010; 29(43):5775-84. DOI: 10.1038/onc.2010.227
Source: PubMed

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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    • "Previous studies have also suggested the possibility that the effect of the L1 insertion may be derived through the action of the ASP promoter (Speek 2001; Nigumann et al. 2002; Weber et al. 2010). Interestingly, it has been shown that an L1 fusion gene transcribed from the ASP may result in a decrease in the nearby gene expression levels (Weber et al. 2010). The L1 ASP is located 0.6 Mb upstream of PRLR coding region and is in the same orientation, which enables the effect of the ASP on PRLR expression. "
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    • "Finally, effects on neighboring gene loci may be important aspects to understand. Specific L1 antisense initiated transcripts can act as oncogenes (Roman-Gomez et al., 2005; Weber et al., 2010). More broadly, Estecio and colleagues recently recognized that gene promoters with high transposon content are also relatively resistant to methylation in cancer cell lines and maintain higher expression levels in that context as compared to loci which are hypermethylated (Estecio et al., 2010). "
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