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Gene scissors find target for testicular cancer therapy

Bonn researchers uncover contribution of protein degradation processes to cisplatin resistance in germ cell tumors

Cisplatin is used successfully in the chemotherapy of testicular cancer. However, patients who develop resistance to the cytostatic drug urgently need alternative therapy options. Researchers at the University Hospital Bonn (UKB) have now been able to elucidate a mechanism underlying cisplatin resistance in testicular cancer. Using CRISPR gene scissors, they identified the NAE1 gene as its driver. Inhibiting this resistance mediator by adding the NAE1 inhibitor MLN4924 not only restores the effect of cisplatin, but also has an additional killing effect on tumor cells. The study results have now been published in the British Journal of Cancer.

Testicular cancer, also known as testicular germ cell tumors (TGCT), is the most common type of cancer in young men. When treated with cisplatin, the tumor cells stop growing and die. This is because the cytostatic drug causes damage to DNA, the carrier of genetic information, thus stopping the cell cycle. “The alarm signal is sent ‘Attention, repair, do not divide further.’ To do this, the cell needs, among others, so-called tumor suppressor genes that put the brakes on precisely this kind of damage and do not release cell growth until it has been repaired,” says Prof. Hubert Schorle from the Institute of Pathology at UKB. The chances of cure with this type of chemotherapy are exceptionally high for testicular cancer. However, in some patients the tumor develops cisplatin resistance, which is associated with a reduced survival rate. 

To get to the bottom of the causes of cisplatin resistance in testicular cancer, the Bonn research team used CRISPR gene scissors.  They used them to activate each gene once in testicular cancer cells. They then treated the genetically modified cell culture with cisplatin and singled out those cells that had survived and in which, as a result, the cytostatic drug was no longer effective. “By analyzing the DNA of these cells, we found where the gene scissors were active and were able to identify the genes responsible for cisplatin resistance. In addition to genes already known for cisplatin resistance, to our surprise we found the gene NAE1, the regulator of the neddylation cascade,” says first author Kai Funke, a PhD student of Prof. Schorle .

A cell must be able to precisely control the type and amount of different proteins. In addition to the regulation of protein production, control over the targeted degradation of proteins is also important. Here, the neddylation cascade marks the proteins destined for degradation. “It appears that tumor suppressor proteins, which act as brakes on cell growth in the presence of DNA damage, are an important target of neddylation. Accordingly, they are degraded to a greater extent and their braking effect is lifted when the neddylation cascade is overactive due to the upregulated gene NAE1,” explains Prof. Schorle, who is also a member of the Transdisciplinary Research Area (TRA) “Life and Health” at the University of Bonn. […]

Participating Core Facilities: The authors acknowledge the support from the Flow Cytometry and Next Generation Sequencing Core Facilities.

Participating institutions and funding:

Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, Bonn, Germany

Institute of Physiology II, University Hospital Bonn, Bonn, Germany

Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Publication: K. Funke et al.: Genome-scale CRISPR screen reveals neddylation to contribute to cisplatin resistance of testicular germ cell tumors; British Journal of Cancer; DOI: https://doi.org/10.1038/s41416-023-02247-5

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