Better treatments for some of the deadliest forms of cancer could be a step closer following a discovery by scientists from the School of Biological Sciences, University of California, Irvine, CA, USA, about how the GLI1 protein is activated in tumor cells.

The results of the study, funded by the National Institute of General Medical Sciences, the National Cancer Institute, and others, were published in Life Science Alliance.[1]

Based on the outcome of the study, the researchers believe that their findings could eventually lead to possible therapies for the especially melanoma and pancreatic adenocarcinoma, as well as the most common types of childhood brain cancer and adult skin cancer.

The GLI1 protein, which is important in cell development but has also been found turned on in various cancers. GLI1 is typically activated by the Hedgehog signaling pathway, known as HH. However, scientists have known for about a decade that crosstalk, or interaction, between HH and the mitogen-activated protein kinase pathway has a role in cancers.

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“In some cases, proteins in one pathway can turn on proteins in another,” explained lead author A. Jane Bardwell, project scientist in UCI’s Department of Developmental and Cell Biology.

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“It’s a complex system. We wanted to understand the molecular mechanism that leads to GLI1 being activated by proteins in the MAPK pathway,” Jane Bardwell said.

GLI1 and SUFA
GLI1 normally binds tightly with a protein called SUFU.  SUFU is a key negative regulator of three GLI transcription factors, which suppresses GLI1, preventing it from penetrating cell nuclei and turning on genes. However, dissociation of SUFU is considered to be a key step in GLI activation.[2]

The scientists examined seven sites on the GLI1 protein that could 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,” noted 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,” Lee Bardwell added.

Significant findings
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. 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,” Lee Bardwell added.

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.

The research was performed in collaboration with the UCI School of Medicine’s Department of Microbiology & Molecular Genetics and the Stanford University School of Medicine’s Department of Dermatology.

Reference
[1] Bardwell AJ, Wu B, Sarin KY, Waterman ML, Atwood SX, Bardwell L. ERK2 MAP kinase regulates SUFU binding by multisite phosphorylation of GLI1. Life Sci Alliance. 2022 Jul 13;5(11):e202101353. doi: 10.26508/lsa.202101353. PMID: 35831023. [Article]
[2] Svärd J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergström A, Ericson J, Toftgård R, Teglund S. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell. 2006 Feb;10(2):187-97. doi: 10.1016/j.devcel.2005.12.013. Erratum in: Dev Cell. 2006 Mar;10(3):409. Henricson, Karin Heby [corrected to Heby-Henricson, Karin]. PMID: 16459298.

Featured image: Scientists at work. Photo courtesy: © 2017 – 2022. Fotolia/Adobe. Used with permission.

 

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