We’re still just getting started here at Oncobites, but the story is already clear: Cancer is complicated. So far Morgan has covered the underlying risk factors of cancer— the environmental and lifestyle factors that influence cancer development. Sara has explained that cancer arises in cells that acquire mutations in the genes that control important cellular functions like proliferation and repair. But the story has additional plot twists. Recent projects to characterize mutations in cancer have discovered that in addition to these well-known mutations, tumors commonly have mutations in epigenetic regulators– genes that regulate how DNA is organized within your cells and how other genes are expressed. So what are these epigenetic regulators and why are they mutated so often in cancer?
Answering these questions requires taking a step back to remind ourselves of the molecular biology of DNA organization. Our genomes, the DNA that encodes for every function of every cell in our bodies, is nearly 2 meters long but must be compacted to fit within the nucleus which is only about 10 microns in diameter. That’s like fitting a 6 foot long string into a space with a diameter 100 times smaller than the period at the end of this sentence. To accomplish this feat, DNA is twisted and turned to efficiently pack it within the nucleus. This compaction is achieved by winding the DNA like a string around a bead-like core of proteins called histones. Chromatin, this association of DNA with histone proteins, is further compacted by coiling up the beads on the string and then further coiling up those coils so that they are packed up tight.
Great! Compacting DNA gets it to fit tidily within the nucleus. However, if DNA is a blueprint with instructions to direct cellular functions, then compacted DNA is like series of long scrolls that must be unrolled to be read. So after going through all the trouble to organize the DNA into neat bundles within the nucleus, the cell has to then unpackage certain bits of DNA (genes and their regulatory elements) in a regulated manner as it needs them and then repackage them when they are no longer needed.
To recap: in order to fit into the nucleus, DNA is wrapped and compacted, but that compaction requires numerous helper proteins to help pack, unpack, and then repackage the DNA as appropriate. Chromatin remodelers, the proteins that do all of this nuclear organization, must be carefully regulated so that the right genes are unpacked and expressed (or replicated or repaired) at the right time and in the right contexts. But how does the cell keep track of what regions should be packed or unpacked? Bookmarks. Chemical groups such as methylation and acetylation (the “bookmarks” of DNA organization), are deposited on the DNA and the histone proteins by “writing” proteins, are interpreted by “reading” proteins, and can be removed by “eraser” proteins. These readers, writers, erasers, and chromatin remodelers (“movers”) work together to regulate the compaction of genes. The compaction of genes, in turn, regulates the expression of genes. These chemical bookmarks can be inherited by the progeny of a cell and establish a separate genetic code in addition to the As, Cs, Ts, and Gs of the DNA blueprint: the epigenetic code (“epi-” from the Greek meaning “over”, but in this case really meaning “in addition to”).
So how is this related to cancer? Each of the epigenetic regulators controls the expression of dozens or hundreds of genes. If the activity of even one reader, writer, eraser, or mover is disrupted, the expression of whole swaths of the genome can be disrupted. And as it turns out, mutations in these genes are common in many different tumor types. What epigenetic regulators are mutated and in which cancers? Well, many of them, affecting every aspect of epigenetic regulation and in most cancers. In one kind of kidney cancer, clear cell Renal Cell Carcinoma, 4 of the top 5 most commonly mutated genes are in epigenetic regulators. Another study found that in melanoma, the most common form of skin cancer, 22% of mutations were in genes encoding epigenetic regulators. The mutations in epigenetic regulators observed in melanoma affected readers, writers, erasers, and movers. Maintenance of appropriate epigenetic factors is so important, and their roles are so ubiquitous that even mutations in genes that wouldn’t normally be considered epigenetic regulators can affect epigenetic processes. Cancers as dissimilar as Acute Myeloid Leukemia (a blood cancer) and glioma (a type of brain cancer) have mutations in a pair of proteins called IDH1 and IDH2. The IDH proteins are enzymes involved in a series of reactions that turn food energy (carbohydrates, fats, and proteins) into cellular energy (ATP). These mutations change the function of the IDH enzymes and cause them to produce a new output. The new enzymatic output inhibits eraser enzymes that remove methylation marks from both DNA and histone proteins. Since the methylation marks can’t be removed, they pile up on the DNA and histones across the entire genome and alter the expression program of genes. These new gene expression programs support cancer development and growth by preventing expression of tumor suppressor genes, the guardians of the genome. Luckily, work is already underway to develop drugs to inhibit the epigenetics modulators that go awry in cancer. Numerous small molecules are in various stages of development to target epigenetic dysregulation in cancer and because one epigenetic modulator can be mutated in many dissimilar cancers, targeting epigenetic regulators might provide us with tools that can be used in the treatment of multiple types of cancer.
Now that we’ve covered some environmental, genetic, and epigenetic causes of cancer– and begun to hint at some of the ways researchers are working to overcome these causes– we have a good foundation to take a deep dive into the depths of cancer and current cancer research.
- Hakimi, A.A., Pham, C.G., & Hsieh, J.J.(2013). A clear picture of renal cell carcinoma. Nature Genetics. doi: 10.1038/ng.2708.
© NIH Common Fund: Epigenetics Mechanisms
Epigenetic Targeted Drug Development: Adapted from original art by Emily Hollis