How a Certain Protein Can Cause Deadly Cancers

A Discovery Headed by the University of California, Irvine Advances the Hunt for Improved Treatments

A discovery made by researchers at the University of California, Irvine on how a certain protein is activated in tumor cells may lead to more effective treatments for some of the most deadly types of cancer. The finding, which was led by scientists at the School of Biological Sciences, may potentially result in treatment options for the especially dangerous melanoma and pancreatic adenocarcinoma, as well as the most common type of childhood brain cancer and adult skin cancer. The study was published in the journal Life Science Alliance.

The GLI1 protein, which is essential for cell development but has also been linked to a number of cancers, was the subject of the finding. The Hedgehog signaling pathway, also known as HH, usually activates GLI1. However, scientists have known for almost a decade that crosstalk, or interaction, between HH and the mitogen-activated protein kinase pathway, has a role in cancer.

Molecular Mechanisms of GLI1 Activation

“In some cases, proteins in one pathway can turn on proteins in another,” said lead author A. Jane Bardwell, a project scientist in UCI’s Department of Developmental and Cell Biology. “It’s a complex system. We wanted to understand the molecular mechanism that leads to GLI1 being activated by proteins in the MAPK pathway.”

GLI1 generally forms a strong bond with a protein known as SUFU. This protein inhibits GLI1, preventing it from penetrating cell nuclei and turning on genes. The researchers examined at seven locations on the GLI1 protein that may be phosphorylated or have a phosphate group transferred onto it.

“We identified three that can be phosphorylated and are involved in weakening the binding between GLI1 and SUFU,” said Lee Bardwell, professor of developmental and cell biology whose laboratory conducted the project. “This process activates GLI1, enabling it to enter the nucleus of cells, where it can cause uncontrolled growth resulting in cancer.”

He noted that phosphorylation of all three sites causes a significantly higher level of GLI1 escape from SUFU than if just one or even two of them receive phosphate groups.

Potential for Personalized Cancer Treatments

The discovery is a significant step toward more effective and personalized cancer treatments. “If we can understand exactly what is going on in a certain cancer or particular tumor, it could be possible to develop a drug specific to a specific tumor or individual patient,” Bardwell said. “It would allow us to treat these diseases without the toxicity of basic chemotherapy.” In addition, many tumors from the same cancer have different mutations among individuals. Eventually, it may be feasible to screen tumors to develop the best approach for each.

Reference: “ERK2 MAP kinase regulates SUFU binding by multisite phosphorylation of GLI1” by A. Jane Bardwell, Beibei Wu, Kavita Y. Sarin, Marian L. Waterman, Scott X. Atwood and Lee Bardwell, 13 July 2022, Life Science Alliance.
DOI: 10.26508/lsa.202101353

The study was funded by the National Institute of General Medical Sciences, the National Cancer Institute, the UC Cancer Research Coordinating Committee, and the Damon Runyon Cancer Research Foundation.

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