After years studying the molecular bases of glioblastoma - the most common brain tumor and one of the most aggressive of all cancers, the group led by Dr. Joan Seoane , Director of Translational Research at the Vall d'Hebron Institute of Oncology (VHIO) and ICREA Research Professor has today published a study in Nature Medicine identifying USP15 as a critical protein in cancer which, thanks to its molecular characteristics, shows enormous therapeutic promise.
USP15 promotes tumor progression by activating the TGFβ pathway. Playing a highly significant oncogenic role in glioblastoma, TGF- is a powerful immunosuppressant allowing the tumor to escape the host immune system. It also acts as an angiogenic factor inducing blood vessels, promotes tumoral invasion, activates cancer stem cells, and in some tumors, induces metastases.
USP15 as a "Biological Thermostat" at the core of a TGFβ chain reaction
Dr. Seoane's team has unmasked the USP15 enzyme as activator of the TGFβ chain reaction. In tumors the USP15-TGF- axis is deregulated due to USP15 gene amplification leading to an aberrant TGF- activation.
USP15 acts by controlling and correcting the TGFβ activity in the same way that a thermostat regulates temperature. If the TGFβ activity is high, it reduces; and if it is low, it increases the TGFβ activity. USP15 therefore achieves optimal TGFβ activity.
Protein stability is regulated through the elimination or aggregation of ubiquitins, small proteins that establish which molecules need to be eliminated. This process is finely regulated by deubiquitinating enzymes (DUBs) such as USP15 which determine the correct level of a protein under certain physiological conditions. In this orchestrated manner, USP15 controls and adapts the TGFβ receptor stability and, therefore, the activity of the pathway.