Renal cell carcinoma (RCC) is the most lethal of the urologic malignancies. We previously discovered that DAB2IP, a novel Ras GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. In this study, we determined the biological functions of DAB2IP in clear cell RCC (ccRCC) and its potential mechanisms of action. Correlations between DAB2IP expression level and ccRCC tumor size and patient survival were analyzed, and the results showed that ccRCC patients with high DAB2IP mRNA level exhibited smaller tumor size and better survival than the patients with low DAB2IP. Compared to control, DAB2IP knockdown significantly increased cell proliferation, promoted cell cycle progression in G1/S phase, and decreased p27 expression. Mechanism studies demonstrated that loss of DAB2IP promoted p27 protein phosphorylation, cytosolic sequestration, and subsequently ubiquitination-mediated degradation in ccRCC cells. Further studies confirmed that the proline-rich domain in C terminal (CPR) of DAB2IP suppressed AKT phosphorylation and p27 phosphorylation on S10. Hence, DAB2IP is essential for p27 protein stabilization in ccRCC, which is at less partly mediated by PI3K/AKT signaling pathway.

肾细胞癌（RCC）是泌尿系统恶性肿瘤中最致命的。我们之前发现 DAB2IP（一种新型 Ras GTP 酶激活蛋白）在 RCC 中经常发生表观遗传沉默，并且 DAB2IP 缺失与 RCC 患者的总生存期相关。在本研究中，我们确定了 DAB2IP 在透明细胞肾细胞癌 (ccRCC) 中的生物学功能及其潜在的作用机制。分析 DAB2IP 表达水平与 ccRCC 肿瘤大小和患者生存之间的相关性，结果显示，DAB2IP mRNA 水平高的 ccRCC 患者比 DAB2IP mRNA 水平低的患者肿瘤尺寸更小，生存更好。与对照相比，DAB2IP 敲除显着增加细胞增殖，促进 G1/S 期细胞周期进展，并降低 p27 表达。机制研究表明，DAB2IP 的缺失会促进 ccRCC 细胞中 p27 蛋白磷酸化、胞质隔离以及随后泛素化介导的降解。进一步的研究证实，DAB2IP C 端 (CPR) 富含脯氨酸的结构域抑制了 S10 上的 AKT 磷酸化和 p27 磷酸化。因此，DAB2IP 对于 ccRCC 中 p27 蛋白的稳定至关重要，而 ccRCC 至少部分由 PI3K/AKT 信号通路介导。