Characterizing the Role of Cereblon (CRBN) in Renal Cell Carcinoma (RCC) Metastasis

Abstract

Cereblon (CRBN), substrate receptor of E3 ubiquitin ligase complex, is involved in the degradation of target proteins through the ubiquitin-proteasome system (UPS). Several studies reported the putative binding partners of CRBN, but still, the role of CRBN in cancer progression, especially in the stage of cancer metastasis is largely unknown. In this study, we characterize the role of CRBN in RCC metastasis. According to our observations, CRBN expression is highly associated with RCC patients' OS and DFS. Supporting the clinical data, migration, and invasion of CRBN deficient RCC cell lines were enhanced, and reverse phenomena were observed when the CRBN is ectopically expressed in RCC. Following the behavior of CRBN modulated RCC cell lines, p38, HSP27 and TAK1 were constantly activated in CRBN deficient RCC cell lines, and downstream cytokine, growth factors, and EMT-related gene expressions were also regulated by the depletion of CRBN. However, migration enhancement of CRBN deficient RCC cell lines was rescued by the treatment of p38 and TAK1 chemical inhibitors, respectively, which implies the regulation of RCC metastasis in CRBN deficient cell lines were mediated by the TAK1-p38 signaling pathway, independent with the increase of intracellular ROS production and the alteration of mitochondrial activity. In summary, CRBN act as a tumor metastasis suppressor through the regulation of the TAK1-p38 signaling pathway in RCC independent of the regulation of ROS homeostasis and mitochondrial activity.