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February 21, 2012

Inhibiting Deubiquitinating Enzyme Decreases Oncogenic TGF-ß Signaling in GBM

  • Scientists have identified ubiquitin-specific peptidase 15 (USP15) as a key regulator of the cancer-promoting transforming growth factor β (TGF-β) in glioblastoma and potentially other cancers. A team led by researchers at Vall d’Hebron Institute of Oncology (VHIO) in Barcelona demonstrated that inhibiting the deubiquitinating enzyme in a mouse model of human glioblastoma multiforme (GBM) effectively decreases TGF-β  activity, resuling in the development of smaller tumors.

    Reporting their results in Nature Medicine, Joan Seoane, M.D., and colleagues, say DUBs such as USP15 represent inherently druggable targets, and work is already ongoing to develop inhibitors of deubiquitinating enzymes. Their published paper is titled “USP15 stabilizes T2GF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma.

    TGF-β has been shown to act as an oncogenic factor in advanced tumors, including glioblastoma, and a number anti-TGF-β agents are undergoing clinical trials. In high-grade glioma, for example, elevated TGF-β activity confers poor prognosis and leads to oncogenic responses that spur cell proliferation, invasion, angio­genesis, and immunosuppression. TGF-β also promotes self renewal of stem-like glioma-initiating cells (GICs).

    At the mechanistic level TGF-β activates a heterodimeric complex formed by TβR-II and TβR-I and triggers an intracellular signaling cascade that is initiated through phosphorylation of the receptor-regulated SMADs, SMAD2, and SMAD3. The signaling pathway is regulated through ubiquitination, a process that is reversed by deubiquitinating enzymes (DUBs). Inhibitors of selected DUBs are already in development as potential drug compounds.

    Starting with an RNAi loss-of-function screen targeting human DUB genes, the team identified the DUB USP15 as a key regulator of TGF-β activity and TGF-β-dependent oncogenesis in GBM. Their studies demonstrated that USP15 forms a complex with SMAD7 and SMURF2, resulting in deubiquitinatation and stabilization of type I TGF-β receptor (TβR-I), which leads to an enhanced TGF-β signal.

    At normal levels of USP15 expression the strength of the TGF-β signal regulates the binding of USP15 to SMAD7, the team found. When the TGF-β signal is only weak, USP15 is brought to the SMAD7-SMURF2–TβR-I complex to protect the TGF-β out­put signal. And when the TGF-β signal is strong, USP15 is released from the SMAD7-SMURF2-TβR-I complex, facilitating degradation of the complex and promoting blockade of the TGF-β signal. “However, when USP15 is aberrantly overexpressed, the USP15-SMURF2 balance is tilted toward USP15, and the output of the TGF-β signal is increased, leading to a hyperactive TGF-β signal,” the investigators explain.

    Importantly, expression analyses of patient-derived glioma samples and also breast cancer samples highlighted a statistically significant correlation between levels of phosphorylated SMAD2 and TβR-I, with USP15. This finding supported the notion that USP15 regulates TGF-β activity both in GBM and also in breast tumors. A number of GBM tumors demonstrated USP15 gene amplification and overexpression of the protein, which was associated with particularly poor patient prognosis. 

    The team also investigated the effect of USP15 in vivo, following the injection patient-derived GICs into the brains of immunocompromised animals. Two of the GIC recipient animals developed tumors with elevated expression of USP15. When neurospheres from these animals were infected with a USP15-targeting shRNA and then reintroduced into immunocompromised mice, far fewer and smaller tumors developed compared with animals receiving neurospheres expressing a control shRNA.

    Promisingly when the investigators treated a glioblastoma cell line with an available broad-spectrum DUB inhibitor PR-619, TβR-I and p-SMAD2 concentrations in these cells decreased due to inhibition of USP15.

    “TGF-β inhibitory compounds are currently being evaluated as anticancer therapeutic agents,” the authors note. “Our results show that USP15 could be considered as a marker of response to anti-TGF-β molecules and also that USP15 could be considered as a therapeutic target because USP15 downregulation or inhibition leads to a decrease in TGF-β activity and oncogenesis.”

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