Epigenetics and Cancer: Making a messy mess messier.

As Carl Zimmer recently (and rightly) pointed out at the end of an article on epigenetics, while the concept of being able to alter our epigenetic profiles for therapeutic purposes is a really attractive concept, our current epigenetic therapy options are very, very messy.

Like I said last week:

Lemme give you an example. Lets say we find out that in people with Ke$ha Disease, their GTiM (Good Taste in Music) gene is underexpressed due to hypermethylation of the surrounding DNA. So, YAY! Thats treatable! We have drugs that could fix that, like 5-aza-2'-deoxycytidine!

Um, well, your DNA is also methylated at lots of other positions for very good reasons. Like, keeping mobile and parasitic DNA silent.

Current epigenetic modifying compounds act globally. We cannot simply target the GTiM gene. Sooo... trade Ke$ha Disease for any kind of cancer or potentially another disease altogether?

A non-Ke$ha paper was just published in Nature Oncology that illustrates this catch-22:

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

You have a nice, normal, human protein called cMet. cMet does lots of nice, normal, helpful things most of the time, but if your cells screw up and start making a lot more cMet than theyre supposed to, that cell can turn into cancer. cMet is a proto-oncogene.

The cMet gene itself is made up of 21 exons (the transcribed RNA is long, but then all the introns are cut out to make the smaller, final mRNA to be transcribed). In the intron between exon 2 and 3, there is a LINE. This LINE is normally 'heavily' methylated, so the LINE is not transcriptionally active...

Until you treat cells with these drugs we use as epigenetic modifiers. Drugs like decitabine and azacytidine we can give some cancer patients to 'turn on' their tumor suppressor genes, demethylate the DNA around this LINE, too, allowing it to come back to life.

This would be 'bad' in and of itself, as now weve got this formerly paralyzed bit of mobile DNA that is active again.

But in the case of this LINE in cMet, the LINE promoter doesnt just make the LINE RNA. It also makes a weird cMet (cMet that lacks the first two normal exons, and has some LINE sequence in it).

Well crap. Drugs that would hopefully help treat some cancers actually turn on a proto-oncogene... Except, the LINE cMet doesnt really work right, since its not the whole, normal protein.

Punchline FAIL: They dont actually explain whether this is a good thing or a bad thing or what the hell is going on.

:-/

But this paper does illustrate a simple point regarding our current attempts at epigenetic modification:

In this study, we showed the demethylation-dependent induction of an illegimate transcript originating from an intronic L1-ASP located in the cMet gene (L1-cMet). This effect was seen in a variety of cell types including HL-60 myeloid leukaemia cells, an established cellular model for the approved indication of azacytidine and decitabine. In addition, drug-induced activation of illegitimate transcription was also observed at additional retroelement promoters with the potential to produce fusion transcripts between retroelements and neighbouring sequences in HL-60 cells (Weber B, unpublished data). Together, our results thus suggest that the epigenetic activation of illegitimate fusion transcripts may be a relatively common consequence of drug-induced demethylation in human cancer cell lines and, potentially, in patients undergoing demethylation therapy.

While the concept of altering epigenetic profiles is friggen cool, we are currently shooting into the dark.

Remember this the next time a woo-meister tries to sell you some epigenetic BS-- Even if what they are pushing works, what is it really doing?