Have you ever wondered how the utterly annoying fruit flies can help you against cancer? If you haven’t, now is the time to stop ridiculing those tiny creatures as they might bring a cancer cure, or so suggest the experts at the Colorado University. As the five-year long study concluded recently, it showed promising results for novel therapeutics for colorectal cancer.

The findings in collaboration with researchers from Heidelberg, Germany, have suggested that specific enzymes can be targeted to attack cancerous cells in cases of colorectal cancer. The lethal protein known as HIF1A helps the proliferation of tumor cells even at low oxygen levels. Currently, no drugs have yet been formulated to inhibit the detrimental effects of this protein.

However, this significant study shows potential of manipulating the activity of two enzymes that can inhibit the activity of this deadly protein. These two enzymes, named as CDK8 and TIP60, are found in fruit flies and the effect they have on HIF1A is identical to that in humans. The findings of this study with a potential clinical application against colorectal cancer were recently published in the journal Cell Reports.

The researchers found that the lethal activity of HIF protein was not carried out single-handedly but it required the co-factors CDK8 and TIP6O.

This collaboration showed that for HIF1-dpenedent genes could only express themselves if TIP60 was present as a co-factor in Drosophila. At close examination, it was observed that the TIP60 complex had a conserved role as a HIF1 transcriptional cofactor in Drosophila as well as human cells particularly in colorectal cancer cells. Furthermore, the investigation proved that HIF1A targets required both TIP60 and CDK8 to work efficiency in low oxygen environment. 

What Is HIF1A And How Is It Deadly?

HIF1A is a shortened name for a gene, Hypoxia Inducible Factor 1 Alpha Subunit, which encodes the above mentioned protein. This protein is a master transcriptional regulator protein which enables cells to thrive under oxygen-deprived regions. While it helps cells to metabolically adapt to oxygen-low regions by regulating cellular homeostasis, the protein also facilitates cancer cells to thrive. Under hypoxic (low oxygen level) conditions, this protein supports the process of tumor angiogenesis which turns normal cells into malignant cells, lending a hand to the tumor for spreading into other regions of the body.

In this maneuvered strategy, the tumor cells cause formation of new blood vessels via angiogenesis. When more blood vessels are formed in low-oxygen regions, they feed the cancer cells by supplying them with oxygen and nutrients. And then the cancer cells divide rampantly and spread to other tissues.

Joaquin Espinosa, co-leader of the molecular oncology program at Cancer Center and scientific director at the CU, said, “When tumors learn how to instruct the body to produce new blood vessels, it’s bad news, because now the tumor can grow very large. Then it can get into the blood stream and that’s bad news because cancers can travel to other places and establish metastasis. Metastasis is what kills people.”

He added that many times cancer studies give exciting results in the lab but when the same is translated into clinical setups, the results can be disappointing. However, this particular study has a potential beyond the laboratory, he said.

Thank The Fruit Flies For Their Contribution

This study was initiated in 2012 when Espinosa and colleague Matthew Galbraith were in New York to deliver a symposium. This symposium was attended by a student from Argentina (who now works in Germany) by the name of Joel Perez-Perri who was already working in establishing a relationship between TIP60 and HIF1A.

While the focus of researchers at CU at that time was on CDK8 enzymes, the findings of Perri demonstrated in fruit flies took the work in the right direction.

After synergizing the global efforts against colorectal cancer causative proteins, the study focus was widened and now two co-factors were found to be facilitating HIF protein in tumor cell proliferation.

Cyclin-dependent kinase 8 (CDK8) proteins have a role in cell cycle regulation. Studies show that if gene is mutated and its expression amplified, it can trigger cancer which was also emphasized on by the study.

Similarly, the function of TIP60, named alternately for histone acetyl transferase (HAT) has an integral role in transcription regulation and other nuclear processes. Over expression of this gene also goes in the favor of a tumor cell which has to be inhibited to stop metastasis of cancer cells.

Now that scientists have pinpointed the effects of two co-factors contributing towards increased activity of HIF1 protein, the oncology researchers have their eyes fixed on the findings to translate into colorectal cancer therapeutics.