Loss of deubiquitylase USP2 triggers development of glioblastoma via TGF-β signaling

Glioblastoma (GBM) is the most aggressive primary brain tumor as one of the deadliest cancers. The TGF-β signaling acts as an oncogenic factor in GBM, and plays vital roles in development of GBM. SMAD7 is a major inhibitor of TGF-β signaling, while the deubiquitination of SMAD7 has been poorly studied in GBM. Here, we found USP2 as a new prominent candidate that could regulate SMAD7 stability. USP2 was lost in GBM, leading to the poor prognosis in patients. Moreover, aberrant DNA methylation mediated by DNMT3A induced the low expression of USP2 in GBM. USP2 depletion induced TGF-β signaling and progression of GBM. In contrast, overexpressed USP2 suppressed TGF-β signaling and GBM development. Specifically, USP2 interacted with SMAD7 and prevented SMAD7 ubiquitination. USP2 directly cleaved Lys27- and Lys48-linked poly-ubiquitin chains of SMAD7, and Lys27-linked poly-ubiquitin chains of SMAD7 K185 mediated the recruitment of SMAD7 to HERC3, which regulated Lys63-linked poly-ubiquitination of SMAD7. Moreover, we demonstrated that the DNMT3A inhibitor SGI-1027 induced USP2, suppressed TGF-β signaling and GBM development. Thus, USP2 repressed development of GBM by inhibition TGF-β signaling pathway via the deubiquitination of SMAD7.

 

Comments：

This passage describes a study on the role of USP2 in glioblastoma (GBM), a highly aggressive primary brain tumor with poor prognosis. The study found that USP2 is a major regulator of the TGF-β signaling pathway in GBM, and its loss is associated with poor prognosis in patients. The authors discovered that aberrant DNA methylation, mediated by DNMT3A, leads to the low expression of USP2 in GBM. Furthermore, the study found that USP2 interacts with SMAD7, a major inhibitor of TGF-β signaling, and prevents its ubiquitination. USP2 directly cleaves Lys27- and Lys48-linked poly-ubiquitin chains of SMAD7, which blocks the recruitment of SMAD7 to HERC3 and inhibits Lys63-linked poly-ubiquitination of SMAD7. Overall, this study suggests that USP2 could be a promising therapeutic target in GBM, and the DNMT3A inhibitor SGI-1027 may be a potential treatment for GBM by inducing the expression of USP2 and suppressing TGF-β signaling.

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Cat.No.	Product Name	Information
S7276	SGI-1027	SGI-1027 (DNA Methyltransferase Inhibitor II) is a DNMT inhibitor with IC50 of 6, 8, 7.5 μM for DNMT1, DNMT3A, and DNMT3B in cell-free assays, respectively. SGI‑1027 induces apoptosis.

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