The interaction of YBX1 with G3BP1 promotes renal cell carcinoma cell metastasis via YBX1/G3BP1-SPP1- NF-κB signaling axis

Abstract

Background Renal cell carcinoma (RCC) is a deadly urological tumor that remains largely incurable. Our limited understanding of key molecular mechanisms underlying RCC invasion and metastasis has hampered efforts to identify molecular drivers with therapeutic potential. With evidence from our previous study revealing that nuclear overexpression of YBX1 is associated with RCC T stage and metastasis, we investigated the effects of YBX1 in RCC migration, invasion, and adhesion, and then characterized its interaction with RCC-associated proteins G3BP1 and SPP1. Methods Renal cancer cell lines, human embryonic kidney cells, and clinical samples were analyzed to investigate the functional role of YBX1 in RCC metastasis. YBX1 knockdown cells were established via lentiviral infection and subjected to adhesion, transwell migration, and invasion assay. Microarray, immunoprecipitation, dual-luciferase reporter assay, and classical biochemical assays were applied to characterize the mechanism of YBX1 interaction with RCC-associated proteins G3BP1 and SPP1. Results Knockdown of YBX1 in RCC cells dramatically inhibited cell adhesion, migration, and invasion. Mechanistic investigations revealed that YBX1 interaction with G3BP1 upregulated their downstream target SPP1 in vitro and in vivo, which led to an activated NF-κB signaling pathway. Meanwhile, knockdown of SPP1 rescued the YBX1/G3BP1-mediated activation of NF-κB signaling pathway, and RCC cell migration and invasion. We further showed that YBX1 expression was positively correlated with G3BP1 and SPP1 expression levels in clinical RCC samples. Conclusions YBX1 interacts with G3BP1 to promote metastasis of RCC by activating the YBX1/G3BP1–SPP1–NF-κB signaling axis. Electronic supplementary material The online version of this article (10.1186/s13046-019-1347-0) contains supplementary material, which is available to authorized users.

Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma

“…Moreover, in other cancer types, patients with mutations of YB-1 and ABCB-1 genes have decreased overall survival time. Recently, a study established the importance of YB-1 in mccRCC cell migration and adhesion by activation of nuclear factor kappa B (NF-κB) signalling pathway [39]. Therefore, it is a logical extension to investigate the association of YB-1/ ABCB-1 and sunitinib-resistance development in mccRCC tumors.…”

Y-Box Binding Proteins in mRNP Assembly, Translation, and Stability Control

“…For some mRNAs, such as that of G3BP1, the data on YB-1 involvement in translational control are contradictive. Some researchers report that YB-1 enhances G3BP1 mRNA translation through binding to the 5 UTR [125,126], while others deny such regulation [127,128]. The difference in conclusions can be explained by the presence or absence of regulatory RBPs whose binding and activity are modulated by YB-1.…”

NF-κB and pSTAT3 synergistically drive G6PD overexpression and facilitate sensitivity to G6PD inhibition in ccRCC

“…The results indicated that the NF-κB signaling pathway, which was demonstrated to be dysregulated and functional in the ROS-related chemotherapeutic resistance of ccRCC cells [24,25], might intervene in the regulation of G6PD expression. To verify this hypothesis, the protein expression pattern of several important functional factors of NF-κB pathway, including p105, p50, p65, pIκBα (S32+S36), and IκBα, which have been proved to participate in signaling transduction and closely link to ccRCC tumorigenesis [24,25,28,41], was examined in NAC-or H 2 O 2treated ACHN, 786-O and Caki-1 cells. The results from Western blot showed that the levels of pIκBα, the most abundant inhibitory molecule of NF-κB [41], were reduced by ROS depletion, but there were increased following ROS accumulation in all these three cells.…”