Back in 1979, Dr. Tony Hunter made the groundbreaking discovery that the addition and subtraction of phosphate molecules to proteins on the amino acid tyrosine allows cells to control when key proteins are active and when they are not. With regard to cancer, he went on to show that growth was switched into an “always-on” mode when these phosphates malfunctioned—thus his work opened the doors to other researchers developing tyrosine kinase inhibitors to fight cancer, such as the antileukemia drug Gleevec.
Like so many researchers, Hunter didn’t stop with discovering the “on switch.” He and his colleagues continued to study the process of phosphorylation. But rather than focus solely on using kinases to add phosphates, they also looked into removing them with proteins called phosphatases, essentially creating on/off switches. Then, in 2015, the Hunter lab developed an antibody to identify and study phosphates bonded to another amino acid called histidine.
Where that has led now is to Hunter—the American Cancer Society Professor at the Salk Institute in La Jolla, Calif.—and his team, together with researchers from Switzerland’s University of Basel and University Hospital Basel, discovering a protein called LHPP that acts as a molecular switch to turn off the uncontrolled growth of cells in liver cancer. The work appeared in print in the journal Nature on March 29.
In this most recent work, the team, led by Dr. Michael Hall of the Biozentrum at the University of Basel, examined these “switches” in a mouse model of hepatocellular carcinoma, the most common form of liver cancer. The team analyzed more than 4,000 proteins in healthy and diseased liver tissue, and when they were done, three proteins stood out: the histidine kinases NME1 and NME2 (which were elevated in tumor cells) and the histidine phosphatase LHPP (which was deficient).
“It is striking that LHPP is present in healthy tissue and completely absent in tumor tissue,” said Dr. Sravanth Hindupur, a postdoctoral researcher at the University of Basel and the paper’s first author. So the researchers explored histidine phosphorylation as a potential cancer target and discovered that levels of protein phosphorylated in histidine were significantly higher in the tumor tissue than in normal liver tissue.
As the Salk Institute notes of the research, NME1 and NME2 were known histidine kinases, and LHPP had been suspected to be a histidine phosphatase. With further experiments, the team verified that not only is LHPP a histidine phosphatase, but it is also a tumor suppressor—essentially an off switch for cancer. Reintroducing LHPP into the liver of the model mice destined to develop tumors prevented the formation of tumors.
The thought is that this tumor suppressor could be useful as a biomarker to help diagnose liver cancer and monitor treatment of the disease. But more than that, it might be relevant for other cancer types. Regardless, the research findings add to the growing body of knowledge about cellular processes that promote and inhibit cancer.
“I think we’ve discovered a new control mechanism for cell proteins that, when disrupted, could be a driver for cancer,” says Hunter, who was one of the authors on the new paper. “It’s exciting because it offers the possibility of new therapeutics or new diagnostics for a cancer that’s basically untreatable—liver cancer—and potentially others, as well.”
Moving on from the mice, the researchers next examined samples from human liver tumors and found a similar pattern: NME1 and NME2 levels were high and LHPP was low compared to healthy liver tissue. Furthermore, the Cancer Genome Atlas database, a collection of RNA sequences obtained from different human cancers, showed that a significant fraction of human liver cancers have low levels of LHPP, and that both disease severity and life expectancy are correlated with LHPP levels.
“The parallels between tyrosine phosphorylation and histidine phosphorylation are what really got me interested in the project,” adds Hunter. “Whether this can be used as a therapeutic avenue, I don’t know. But the fact that it could be so disease-relevant motivates me.”