Imagine trying to study Earth, and only looking at the land. You could learn many things, it’s true – but you would also miss a heck of a lot, because the vast majority of our planet is covered by water! They don’t call it the blue planet for nothing!
To quote Homer Simpson: “Doh!”
Now, imagine you’re a scientist studying human genes, looking for a way to cure prostate cancer. You could learn many things by studying the genes that make the code that becomes proteins: our building blocks – or, you might say, our hardware.
But these protein-coding genes make up just 2 percent of our human genome. The other 98 percent are “non-coding.” Not too long ago, says PCF-funded investigator Hui Li, Ph.D., of the University of California-San Francisco, scientists thought these genes were just “junk,” the genetic equivalent of background noise, or satellites floating around in space. But now, Li and an increasing number of scientists believe, “these non-coding genes play a very important role in many cellular processes, including the development and progression of cancer.”
Doh!
These non-coding genes that don’t make proteins make something else that is important: RNA. “They’re like the hidden software of our bodies,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation (PCF). It turns out that these genes – our very own “dark matter,” or “dark DNA” – might not make the difference between getting cancer and not getting it, but they might make the difference between getting cancer that’s easy to cure and cancer that is much more likely to be lethal. “There’s a lot of genetic software running in the background,” adds Simons. “If you have a single letter wrong, it can set you up for trouble. Some of those changes in code might mean you have higher cholesterol, and then a higher chance of having a heart attack or stroke. But that one letter could also change the command for cancer to grow fast or grow slowly; if you have cancer, it could mean you have a much higher chance of having a bad one – one that will go at 75 miles per hour, instead of maybe 25.”
In choosing to study the dark DNA, these non-coding genes, Li says, he has often felt like he’s been looking for treasure in the middle of the desert. Or maybe, searching for that proverbial needle, not in one haystack, but hiding among thousands of haystacks. In research with his mentors, Felix Feng, M.D., and Peixuan Guo, Ph.D., Li has painstakingly looked at thousands of RNA-sequencing genes. This kind of work wouldn’t have been possible even a few years ago, notes Li. “Because of the advancement of next-generation sequencing technology, we now have the bioinformatics and the ability to analyze these novel genes.”
Many genetics studies are like a game of “spot the misspelled word” – on steroids, a task akin to speeding through the Encyclopedia Brittanica, one letter at a time, looking for something that is wrong or out of place.
Li’s work is more like a genetic game of, “Where’s Waldo?” Except he didn’t know what Waldo looked like. But he may have found Waldo, after all: a suspicious gene called SChLAP1-AS.
SChLAP1-AS is a “long non-coding RNA” gene that is “highly expressed in prostate cancer, and is highly prognostic for metastasis,” explains Li. It is “only guilty by its presence. We have identified that SChLAP1-AS is more closely associated with the progression of prostate cancer than any other protein-coding or non-coding gene in our patient cohort.”
Imagine a series of photos of arson fires – and, off to the side, the same shifty-looking guy is always there, looking away from the camera, trying to hide his Zippo lighter. Coincidence? Li thinks not. Especially because, in further study, he found that “if we inhibit this gene in prostate cancer cells, the cells will become less oncogenic. There is less proliferation of cancer. Could we use this gene to turn back the disease, or halt its progression? We want to see whether this gene can be employed as a novel therapeutic target.” He also believes it could become a prognostic biomarker: the presence of SChLAP1-AS in prostate cancer when it is first diagnosed could tell doctors: this cancer is going to be aggressive. Don’t do active surveillance; treat it aggressively. Maybe it could even be looked for earlier, as in: This young man has a bad gene; he needs to start checking for prostate cancer at an earlier age, and he needs to be tested every year.
With The John & Daria Barry Foundation PCF VALOR Young Investigator Award, Li is studying SChLAP1-AS in genetically engineered mice and in human cell lines. He believes this is just the beginning of looking at RNA-coding genes in personalized medicine. “We think studying this gene,” and learning how to block it, “will enhance our understanding of prostate cancer biology in a subset of patients with aggressive disease.” But even more than that: “The non-coding genome was considered undruggable before,” says Li. “If we can make a real breakthrough in this area – hit a previously unknown target – it may also mean a breakthrough in how we treat patients with other forms of cancer, like pancreatic cancer and brain cancer, which share some common traits with prostate cancer, as well.”
