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 TGF¥â 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 TGF¥â chain reaction
Dr. Seoane's team has unmasked the USP15 enzyme as activator of the TGF¥â 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 TGF¥â activity in the same way that a thermostat regulates temperature. If the TGF¥â activity is high, it reduces; and if it is low, it increases the TGF¥â activity. USP15 therefore achieves optimal TGF¥â 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 TGF¥â receptor stability and, therefore, the activity of the pathway.
The problem arises when, in some tumors, the USP15 gene is amplified due to genetic mutations and the enzyme is over produced. The thermostat breaks down and is therefore only sensing the "cold" resulting in the overactivation of the TGF¥â pathway. Remarkably, this is not only a phenomenum of glioblastomas since the USP15 gene has also been found activated in other types of cancer such as breast or ovarian cancer.
Dr. Joan Seoane explained "When we inhibited USP15 in a real model of human glioblastoma, TGF¥â activity decreased and the tumor did not develop. USP15 regulates tumor progression and is critical in cancer."
DUBs (deubiquitinating enzymes): a novel avenue in therapeutic targets
Sometimes potentially powerful therapeutic targets are found but are not pharmacologically accessible due to their biochemical characteristics. "Enzymes in general - particularly deubiquitinating enzymes (DUBs) such as USP15, can easily be deactivated and are therefore good therapeutic targets", Seoane commented, "our results, generated thanks to the funding received from the Spanish Association Against Cancer (AECC), show exciting new promise in improved treatment of cancer patients.".For further information:
Amanda Wren | EurekAlert!
Europe’s Demographic Future. Where the Regions Are Heading after a Decade of Crises
10.08.2017 | Berlin-Institut für Bevölkerung und Entwicklung
Scientists reveal source of human heartbeat in 3-D
07.08.2017 | University of Manchester
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
Researchers from the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science, the Italian Space Agency (ASI), and the Instituto Geofisico--Escuela Politecnica Nacional (IGEPN) of Ecuador, showed an increasing volcanic danger on Cotopaxi in Ecuador using a powerful technique known as Interferometric Synthetic Aperture Radar (InSAR).
The Andes region in which Cotopaxi volcano is located is known to contain some of the world's most serious volcanic hazard. A mid- to large-size eruption has...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
16.08.2017 | Physics and Astronomy
16.08.2017 | Materials Sciences
16.08.2017 | Interdisciplinary Research