Endocrine Abstracts

Ectopic secretion of adrenocorticotropin (ACTH), from sites such as small cell lung cancer (SCLC), results in severe Cushing's syndrome. ACTH is cleaved from pro-opiomelanocortin (POMC). The syndrome occurs when the highly tissue-specific promoter of POMC is activated. This promoter lies within a defined CpG island. CpG islands are usually considered to be unmethylated in all tissues. We hypothesised that changes in promoter DNA methylation might direct aberrant expression of POMC. DNA methylation is associated with silencing of gene expression either by the direct hindrance of transcription factor binding or through the recruitment of histone deacetylases and the condensation of chromatin.

Intriguingly, much of the POMC promoter is methylated in normal non-expressing tissues, in contrast to all somatically-expressed CpG island promoters reported to date. In contrast it is specifically unmethylated in expressing tissues. Methylation in vitro is sufficient for silencing of expression, which is not reversed by inhibition of histone deacetylases, suggesting that other mechanisms account for silencing. Indeed, the response element for E2F factors, which have been shown to be involved in the expression of POMC in SCLC, is methylated in non-expressing tissue but unmethylated in expressing tissue. Moreover, methylation near the response element for the POMC activator Ptx1, diminishes POMC expression, and reduces Ptx1-binding. SCLC cells also appear to lack POMC demethylating activity, implying that demethylation and expression is likely to occur early in, or prior to, neoplastic transformation, and that targeted de-novo methylation might be a potential therapeutic strategy.

These studies give insight into the ectopic expression of POMC and challenge some of the current thinking concerning CpG islands. On going studies are assessing the role of DNA methylation in the long-term feedback suppression of POMC in corticotrophs. What governs the changes in methylation patterns we have observed remains, however, a mystery.