Zhou Aidong, Lin Kangyu, Zhang Sicong, Ma Li, Xue Jianfei, Morris Saint-Aaron, Aldape Kenneth D, Huang Suyun
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
EMBO Rep. 2017 Aug;18(8):1318-1330. doi: 10.15252/embr.201643124. Epub 2017 Jun 16.
Aberrant activation of the Hedgehog (Hh) signaling pathway drives the tumorigenesis of multiple cancers. In this study, we screened a panel of deubiquitinases that may regulate the Hh pathway. We find that deubiquitinase USP48 activates Gli-dependent transcription by stabilizing Gli1 protein. Mechanistically, USP48 interacts with Gli1 and cleaves its ubiquitin off directly. In glioblastoma cells, knockdown of USP48 inhibits cell proliferation and the expression of Gli1's downstream targets, which leads to repressed glioblastoma tumorigenesis. Importantly, USP48's effect on cell proliferation and tumorigenesis depends to some extent on Gli1. In addition, we find that the Sonic Hedgehog (SHH) pathway induces USP48 expression through Gli1-mediated transcriptional activation, which forms thus a positive feedback loop to regulate Hh signaling. In human glioblastoma specimens, the expression levels of USP48 and Gli1 proteins are clinically relevant, and high expression of USP48 correlates with glioma malignancy. In summary, our study reveals that the USP48-Gli1 regulatory axis is critical for glioma cell proliferation and glioblastoma tumorigenesis.
刺猬索尼克（Hh）信号通路的异常激活驱动多种癌症的肿瘤发生。在本研究中，我们筛选了一组可能调节Hh通路的去泛素化酶。我们发现去泛素化酶USP48通过稳定Gli1蛋白来激活Gli依赖的转录。从机制上讲，USP48与Gli1相互作用并直接去除其泛素。在胶质母细胞瘤细胞中，敲低USP48会抑制细胞增殖以及Gli1下游靶点的表达，从而导致胶质母细胞瘤肿瘤发生受到抑制。重要的是，USP48对细胞增殖和肿瘤发生的影响在一定程度上依赖于Gli1。此外，我们发现音猬因子（SHH）通路通过Gli1介导的转录激活诱导USP48表达，从而形成一个正反馈环来调节Hh信号。在人类胶质母细胞瘤标本中，USP48和Gli1蛋白的表达水平与临床相关，且USP48的高表达与胶质瘤恶性程度相关。总之，我们的研究表明USP48 - Gli1调节轴对胶质瘤细胞增殖和胶质母细胞瘤肿瘤发生至关重要。
