Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China.
Cell Death Dis. 2019 Mar 15;10(4):254. doi: 10.1038/s41419-019-1488-2.
Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, and the incidence of RCC continues to rise worldwide. Although RCC can be treated with surgery at an early stages, the five-year survival rates have been observed to decline dramatically in patients with advanced disease. Most patients with RCC treated with cytotoxic or targeted drugs will develop resistance at some point during therapy. Thus, it is necessary to identify novel therapeutic targets for RCC. Here, we found that RANBP2-type and C3HC4-type zinc finger-containing 1 (RBCK1) expression was upregulated in human RCC samples. Analysis of multiple public databases revealed the correlation between RBCK1 expression and poor prognosis in RCC patients. Subsequently, we performed RBCK1 depletion experiments in RCC cells that severely affected the in vivo and in vitro proliferation of renal cancer cells. The effects of RBCK1 on cell proliferation could be rescued with p53 expression knockdown in two cell lines expressing wild-type p53. Further experiments demonstrated that RBCK1 could facilitate p53 poly-ubiquitination and degradation by direct interaction with p53. Together, our results show that RBCK1 may serve as a promising target for RCC therapy by restoring p53 functions.
肾细胞癌 (RCC) 约占成人恶性肿瘤的 3%，并且全球范围内 RCC 的发病率持续上升。尽管在早期阶段可以通过手术治疗 RCC，但在患有晚期疾病的患者中，五年生存率已观察到显著下降。大多数接受细胞毒性或靶向药物治疗的 RCC 患者在治疗过程中的某个时间点会产生耐药性。因此，有必要确定 RCC 的新治疗靶点。在这里，我们发现 RANBP2 型和 C3HC4 型锌指蛋白 1 (RBCK1) 在人 RCC 样本中的表达上调。对多个公共数据库的分析揭示了 RBCK1 表达与 RCC 患者预后不良之间的相关性。随后，我们在 RCC 细胞中进行了 RBCK1 耗竭实验，严重影响了肾癌细胞的体内和体外增殖。在两个表达野生型 p53 的细胞系中，通过 p53 表达敲低可以挽救 RBCK1 对细胞增殖的影响。进一步的实验表明，RBCK1 可以通过与 p53 的直接相互作用促进 p53 的多泛素化和降解。总之，我们的研究结果表明，通过恢复 p53 功能，RBCK1 可能成为治疗 RCC 的有前途的靶点。
