SPOP 通过作为肾癌中的关键调控枢纽促进肿瘤发生。
SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer.
机构信息
Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
出版信息
Cancer Cell. 2014 Apr 14;25(4):455-68. doi: 10.1016/j.ccr.2014.02.007. Epub 2014 Mar 20.
Hypoxic stress and hypoxia-inducible factors (HIFs) play important roles in a wide range of tumors. We demonstrate that SPOP, which encodes an E3 ubiquitin ligase component, is a direct transcriptional target of HIFs in clear cell renal cell carcinoma (ccRCC). Furthermore, hypoxia results in cytoplasmic accumulation of SPOP, which is sufficient to induce tumorigenesis. This tumorigenic activity occurs through the ubiquitination and degradation of multiple regulators of cellular proliferation and apoptosis, including the tumor suppressor PTEN, ERK phosphatases, the proapoptotic molecule Daxx, and the Hedgehog pathway transcription factor Gli2. Knockdown of SPOP specifically kills ccRCC cells, indicating that it may be a promising therapeutic target. Collectively, our results indicate that SPOP serves as a regulatory hub to promote ccRCC tumorigenesis.
缺氧应激和缺氧诱导因子（HIFs）在广泛的肿瘤中发挥重要作用。我们证明，编码 E3 泛素连接酶组件的 SPOP 是透明细胞肾细胞癌（ccRCC）中 HIFs 的直接转录靶标。此外，缺氧导致 SPOP 在细胞质中的积累，这足以诱导肿瘤发生。这种致癌活性是通过细胞增殖和凋亡的多个调节剂的泛素化和降解来实现的，包括肿瘤抑制因子 PTEN、ERK 磷酸酶、促凋亡分子 Daxx 和 Hedgehog 途径转录因子 Gli2。SPOP 的敲低特异性杀死 ccRCC 细胞，表明它可能是一个有前途的治疗靶点。总的来说，我们的研究结果表明，SPOP 作为一个调节枢纽促进 ccRCC 的肿瘤发生。
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