The epigenetics of cancer

I’ve taken an embarrassingly long break from blogging, thanks in part to several big changes in my life. Since I last posted here (in January—egads!) I’ve bought my first home, given birth to a son (his name is Dean) and begun teaching a health journalism class at CUNY. But now I’m back writing again, at least part-time, so I thought I’d revisit my favorite old PLoS haunt. I also have to give due thanks to fellow PLoS blogger John Rennie—he gave an inspiring talk to my class yesterday and reminded me that, yes, I do like this thing called blogging and I would like to do it again sometime. So: hi, everyone!

A long while back, here on this very site, I wrote about how frustrated I get when people claim that the only way a substance can cause cancer is if it directly breaks DNA or other molecular bonds. In that post I was singling out a column Michael Shermer had written for Scientific American arguing why cell phones can’t possibly cause cancer; while I don’t necessarily think that cell phones do cause cancer, I nevertheless get red-faced when people invoke non-scientific arguments to make their case.

In my post, I discussed the possibility that cancer can also have epigenetic causes. For instance, something that affects the expression of genes involved in the cell cycle could in theory cause cells to begin to divide uncontrollably. As I wrote,

Cell cycle genes can be disrupted because of a mutation or a DNA break, sure, but problems could also arise when, say, something causes a tumor-suppressor gene like p53 (which protects against cancer) to be downregulated, perhaps from a post-translational modification or a change to chromatin structure. Or maybe something in the environment ramps up the expression of a growth-promoting gene, causing a cell to abnormally proliferate. Environmental influences could also disrupt the DNA repair machinery, as this would allow DNA breaks that arose as a result of some other process to go unfixed.

Now, when I was writing all that, I was basically just speculating based on my (very spotty) understanding of cancer biology. But there is now increasing evidence that this is correct. As I wrote this month in a news story for Nature Medicine (sorry—it’s behind a paywall), scientists have recently discovered several new molecules that thwart cancer in animals by manipulating epigenetic processes.

Let me take a step back to explain these findings. For decades, scientists have known that a gene called MYC plays a role in certain cancers. MYC is a transcription factor; it manipulates the activity of key cell cycle genes—it’s kind of like a genetic manager that ensures that cells don’t start dividing willy-nilly and become tumors. One of the ways MYC manages its underling genes is by adding and removing special stamps (called acetyl-lysine residues) to and from the DNA immediately surrounding them. Other proteins—known as bromodomain proteins—recognize these stamps and subsequently increase or decrease the expression of the surrounding genes. When MYC activity gets ramped up too high for some reason, MYC turns into what I’ll call Crazy-MYC. It stops managing its cell cycle genes effectively, putting stamps where they shouldn’t be—ultimately causing cells to go haywire and divide when they shouldn’t.

As my Nature Medicine piece explains, researchers have now developed several new molecules that prevent cancer in part because they interfere with the ability of bromodomain proteins to read Crazy-MYC’s unnecessary stamps. Suddenly, Crazy-MYC’s crazy stamping isn’t so dangerous anymore; the cell just kind of ignores it. Researchers have tested these molecules in animal models of several different cancers (mostly blood cancers) and have found that they significantly improve survival. (To make things even more complicated, research suggests that these molecules also inhibit the expression of MYC itself and several other cancer-causing genes, but I’m not going to get into that here.)

So how does this relate back to my original point about epigenetics? These molecules don’t prevent cancer because they have anything to do with mutations or DNA breaks—they are simply chemicals that influence gene expression. So it makes sense that a chemical or exposure that affects gene expression in the opposite way could perhaps cause cancer. It wouldn’t have to mess with DNA directly; it could simply enhance the ability of bromodomain proteins to read acetyl-lysine stamps, or mimic Crazy-MYC’s crazy stamping; you get my drift. My point: cancer is about far more than just mutations.


Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, & Mitsiades CS (2011). BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 146 (6), 904-17 PMID: 21889194

Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, & Vakoc CR (2011). RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature, 478 (7370), 524-8 PMID: 21814200

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10 Responses to The epigenetics of cancer

  1. J. Randy Macdonald, PhD. says:

    Nice piece touching on just one important aspect of epigenetics and cancer. One small quibble about this sentence: “One of the ways MYC manages its underling genes is by adding and removing special stamps (called acetyl-lysine residues) to and from the DNA immediately surrounding them”. As I understand it, acetyl-lysines are added to the histones around which the DNA is folded and not to the actual DNA molecule. A minor point, but important to biochemists such as myself. 😉

  2. Thanks, Randy, and very good point — the acetyl-lysines are indeed being added to the histones, not the DNA. As you can probably tell, I’m just starting to learn about this stuff, and it sounds like you know quite a lot more. If you’re interested, I’d love for you to point me towards other important research highlighting the role of epigenetics in cancer. Thank you!

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  4. Nice piece. You should have a look at this article as well: and tell us what you get from it. Lind wants to use a small set of methylation biomarkers as a diagnostic tool in colorectal cancer. Does this indicate that epigenetic alterations are the main cause of colorectal cancer?

  5. mack says:

    -I nevertheless get red-faced when people invoke non-scientific arguments to make their case-

    Religious devotion to anything can be dogmatic

  6. Chris says:

    Hey Melinda — nice post. Thought I’d give you a heads-up that it’s had unintentional consequences, though. It seems that the cell-phones-cause-cancer conspiracy theorists have latched onto your (accurate) statement pointing out that cancer doesn’t necessarily involve changes to DNA proper.

    I won’t link here, but if you search “EMF cancer epigenetics”, you’ll see what I mean. If I may, I think you can clear it up by pointing out that there’s no physical mechanism connecting epigenetics and non-ionizing radiation. Just sayin’. Later.

  7. Pingback: Epigenetics – You Bring Your Own Goofy Preconceptions to IT | Epigenetics Experts Blog

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  9. Doug says:

    A very nice article. Epigenetics is a topic relatively new to me as well. However, there is some pretty strong support for the role damage to the epigenome plays in causing cancer. There seems to be some relatively new treatments for epigenetic damage showing promise in cancer.