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

Glioblastoma (GBM) is the most aggressive primary brain tumor as one of the deadliest cancers. The TGF-beta signaling acts as an oncogenic factor in GBM, and plays vital roles in development of GBM. SMAD7 is a major inhibitor of TGF-beta 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-beta signaling and progression of GBM. In contrast, overexpressed USP2 suppressed TGF-beta 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-beta signaling and GBM development. Thus, USP2 repressed development of GBM by inhibition TGF-beta signaling pathway via the deubiquitination of SMAD7.

Automated summary

This study identified USP2 as a new candidate gene that inhibits the development of GBM by deubiquitinating SMAD7 and suppressing the TGF-beta signaling pathway.