SAG (Sensitive to Apoptosis Gene) and ROC1 (Regulator of Cullin-1) are two family members of the RING component of CRL (Cullin RING ligase). Both members are essential for growth and survival of several types of human cancer cells; their role in renal cell carcinoma (RCC), however, remains elusive. Here we reported that compared to adjacent normal tissues, both SAG and ROC1 are overexpressed in RCC, which is positively correlated with poor patient survival, particularly for SAG. Depletion of SAG or ROC1 inhibited growth and survival of RCC cells by inducing G2/M arrest, senescence, and apoptosis likely due to accumulation of WEE1, p21, p27, NOXA, and BIM. Interestingly, simultaneous BIM knockdown in RCC cells partially rescues growth suppression triggered by depletion of SAG, but not ROC1, suggesting a differential role of BIM. Collectively, our study provides the proof-of-concept evidence that RING components of CRL are attractive candidates for targeted therapy of RCC.

SAG（对凋亡基因敏感）和ROC1（Cullin-1的调节子）是CRL（Cullin RING连接酶）的RING成分的两个家族成员。两种成员对于几种类型的人类癌细胞的生长和存活都是必不可少的。然而，它们在肾细胞癌（RCC）中的作用仍然难以捉摸。在这里，我们报道，与邻近的正常组织相比，SAC和ROC1在RCC中均过表达，这与不良的患者生存率呈正相关，特别是对于SAG。SAG或ROC1的耗尽通过诱导G2 / M停滞，衰老和凋亡而抑制RCC细胞的生长和存活，这可能是由于WEE1，p21，p27，NOXA和BIM的积累引起的。有趣的是，RCC细胞中同时发生的BIM敲低可以部分挽救由于SAG耗尽而引起的生长抑制，但ROC1却不起作用，这提示BIM的作用不同。总的来说，