USP15 Promotes Brain Cancer by Activating the TGF-beta Pathway

It plays a role in immunity, cancer, heart disease, and diabetes. TGF-beta acts as an antiproliferative factor in normal epithelial cells and at early stages of cancer development. In normal cells, TGF-beta, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, parts of the TGF-beta signaling pathway are mutated, and TGF-beta no longer controls the cell. These cancer cells and surrounding stromal cells (fibroblasts) begin to proliferate. Both types of cell increase their production of TGF-beta. This TGF-beta acts on the surrounding stromal cells, immune cells, endothelial, and smooth muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive. TGF-beta also converts effector T-cells, which normally attack cancer with an inflammatory reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction.

USP15 was also found to stabilize type I TGF-beta receptor (TbetaR-I), leading to an enhanced TGF-beta signal. High expression of USP15 correlated with high TGF-beta activity, and the USP15 gene was found to be amplified in glioblastoma, breast, and ovarian cancer. USP15 amplification conferred poor prognosis in individuals with glioblastoma.

The important role of USP15 was confirmed by the finding that downregulation or inhibition of USP15 in a patient-derived mouse model of glioblastoma decreased TGF-beta activity. Moreover, depletion of USP15 decreased the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-beta signaling.

Senior author Dr. Joan Seoane, director of translational research at the Vall d'Hebron Institute of Oncology, said, “When we inhibited USP15 in a real model of human glioblastoma, TGF-beta activity decreased and the tumor did not develop. USP15 regulates tumor progression and is critical in cancer.”

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Vall d'Hebron Institute of Oncology