Tu Yiming, Xu Lei, Xu Jia, Bao Zhongyuan, Tian Wei, Ye Yangfan, Sun Guangchi, Miao Zong, Chao Honglu, You Yongping, Liu Ning, Ji Jing
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
Oncogene. 2022 Apr;41(18):2597-2608. doi: 10.1038/s41388-022-02275-0. Epub 2022 Mar 25.
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.
胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤，也是最致命的癌症之一。转化生长因子-β（TGF-β）信号在GBM中作为一种致癌因子，在GBM的发展中起着至关重要的作用。SMAD7是TGF-β信号的主要抑制剂，而SMAD7的去泛素化在GBM中的研究较少。在这里，我们发现泛素特异性蛋白酶2（USP2）是一个新的重要候选因子，可调节SMAD7的稳定性。USP2在GBM中缺失，导致患者预后不良。此外，由DNA甲基转移酶3A（DNMT3A）介导的异常DNA甲基化诱导了GBM中USP2的低表达。USP2的缺失诱导了TGF-β信号和GBM的进展。相反，过表达的USP2抑制了TGF-β信号和GBM的发展。具体而言，USP2与SMAD7相互作用并阻止SMAD7泛素化。USP2直接切割SMAD7的赖氨酸27和赖氨酸48连接的多聚泛素链，而SMAD7 K185的赖氨酸27连接的多聚泛素链介导SMAD7向含E3泛素连接酶3（HERC3）的募集，从而调节SMAD7的赖氨酸63连接的泛素化。此外，我们证明DNMT3A抑制剂SGI-1027诱导USP2，抑制TGF-β信号和GBM的发展。因此，USP2通过去泛素化SMAD7抑制TGF-β信号通路，从而抑制GBM的发展。
