Discovered a key protein in tumor metastasis

Discovered a key protein in tumor metastasis https://i0.wp.com/www.eresviral.com/wp-content/uploads/2018/10/Descubierta-una-proteína-clave-en-la-metástasis-tumoral.jpg?fit=192%2C146&ssl=1

Discovered a key protein in tumor metastasis







A team of researchers from the Cancer Program at the Hospital del Mar Institute for Medical Research (IMIM) (Catalonia, Spain), led by Víctor M. Díaz and Antonio García de Herreros, has identified a key enzyme in the development of cancer called USP27X.



In this work, published in the journal Cancer Research, scientists have carried out a genomic analysis to find new regulators of the Snail1 protein, a key switch in tumor invasion. Experts have discovered the enzyme USP27X that increases the stability of Snail1 and allows the tumor cell to start the process called epithelial-mesenchymal transition (or EMT, for its acronym in English). This mechanism gives the tumor cells the ability to invade neighboring tissues and form metastases; It also increases drug resistance.



A few years ago, researchers determined how normal epithelial cells kept Snail1 levels down because of their continued degradation in the proteasome, an enzyme complex that acts as a 'protein graveyard' within the cell.



The degradation of Snail1 is ordered by the incorporation of a molecular brand called ubiquitin. Thanks to the enzyme USP27X, the tumor cells prevent the degradation of Snail1 by eliminating the ubiquitins. When Snail1 loses this destruction mark, it can not degrade and accumulate in the cell. The tumor cells use the USP27X to increase the amount of Snail1, which allows to start a cellular program that allows them to invade better and form more metastases.







On the left, detection of metastases of breast cancer cells that emit light in the lungs of mice. On the right, unmodified tumor cells (above) and tumor cells without USP27X (below), the metastases are marked with circles. (Photo: UPF)



"If we inhibit USP27X we can regulate the levels of Snail1, and, therefore, control its negative effects on proliferation, invasion and metastasis," says Diaz, director of research and researcher at Pompeu Fabra University (UPF). "USP27X is an enzyme, so we can design inhibitors that in the future would allow to restore the levels of Snail1 and block the EMT," he adds.



Experiments done in mice with tumor cells that emit light (as indicated in the red picture) show how they form metastases in the lung (marked with circles in the figure). On the other hand, if we eliminate the USP27X, the appearance of metastasis is completely blocked.



Another relevant aspect has to do with drug resistance associated with the expression of Snail1 and USP27X. Breast cancer cells become resistant to treatment with cisplatin, a drug often used to fight this type of cancer.



"When we inhibit USP27X, we are able to reverse the resistance to cisplatin treatment and again make the tumor cells sensitive," says Guillem Lambies, first author of the article. "These results open the door to generating drugs that by inhibiting USP27X can combat chemoresistance."



The same group, in collaboration with Joaquín Arribas of the Vall d'Hebron Institute of Oncology (VHIO), has analyzed the expression of Snail1 and USP27X in tumors derived from patients with breast cancer. They have found a positive correlation between the two proteins, especially in those more aggressive tumors, called triple negatives.



These triple negative breast tumors are especially resistant to chemotherapy and have a worse prognosis. The researchers believe that new drugs designed to inhibit USP27X activity may have a promising future over these types of tumors. The group of Diaz and Garcia de Herreros are currently working to find inhibitory molecules of the USP27X that can reverse the negative effects of Snail1. (Source: UPF)

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