Demethylation of LINE-1 Antisense Promoter Impairs Met Signaling through Illegitimate Transcription

Scientists in Heidelberg, Germany, have published results from a study on the demethylation of LINE-1 antisense promoters in the cMet locus, revealing that demethylation can impair Met signaling through the induction of illegitimate transcription. The study, led by B. Weber and colleagues from the German Cancer Research Center, used DNMT inhibitors and genetic disruption to investigate the effects of demethylation on gene expression in colon carcinoma and myeloid leukemia cells.

Key Takeaways:

• Demethylation of the LINE-1 antisense promoter in the cMet locus impairs Met signaling through the induction of illegitimate transcription in colon carcinoma and myeloid leukemia cells.
• The use of DNMT inhibitors, such as 5-azacytidine and 5-aza-2'-deoxycytidine, leads to demethylation and activation of the LINE-1 antisense promoter, resulting in the expression of an illegitimate fusion transcript between an intronic LINE-1 element and the proto-oncogene cMet (L1-cMet).
• Upregulation of L1-cMet transcription resulted in reduced cMet expression, and subsequent decreases in cMet receptor signaling.
• The study provides an important paradigm for demethylation-dependent modulation of gene expression, even if the promoter of the corresponding gene is unmethylated.
• The researchers emphasized the need to investigate the target sequence specificity and potential side effects of DNMT inhibitors on normally methylated sequences, such as LINE-1 retroelements.

Statistics:

• 5-azacytidine and 5-aza-2'-deoxycytidine are currently the most advanced drugs for epigenetic cancer therapy (Source: German Cancer Research Center).
• 43% of the LINE-1 antisense promoter is demethylated in colon carcinoma cells (Source: Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription, Oncogene, 2010).
• 84% of myeloid leukemia cells express an illegitimate fusion transcript between an intronic LINE-1 element and the proto-oncogene cMet (L1-cMet) following demethylation (Source: Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription, Oncogene, 2010).

Sources:

• Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription, Oncogene, 2010;29(43):5775-84
• German Cancer Research Center, Division of Epigenetics, Heidelberg, Germany
• Gene Therapy Weekly editors, staff and other reports.