The lack of preventive measures for renal cell carcinoma (RCC) lung metastasis and effective treatments for metastatic RCC is currently an unmet clinical need that needs to be addressed. The DNA methylation profiling of primary RCC with matched lung metastases remains unclear, which could lead to novel biomarkers and therapeutic targets that may limit the metastasis of renal cancer. In this study, extended-representation bisulfite sequencing and transcriptome sequencing were performed on primary RCC with matched lung metastases to identify metastasis-related genes associated with DNA methylation. Among these genes, reticulocalbin 3 (RCN3) was associated with RCC progression. We found that promoter hypomethylation can upregulate the expression of RCN3. The upregulation of RCN3 can promote the malignant phenotype of RCC in vitro while promoting RCC lung metastasis in vivo. We also demonstrate that RCN3 interacts with MMP10 through its EF-hand 5–6 domains, which promotes the secretion of MMP10 and activates the PI3K/Akt pathway. Finally, we identified that Carboxy-pyridostatin 2HCl may inhibit the metastasis of RCC by binding to the pocket at the binding interface between RCN3 and MMP10. Together, these findings suggest that RCN3 is hypomethylated and upregulated in RCC lung metastasis and plays an important role in RCC lung metastasis, which may serve as a potential therapeutic target. • DNA methylation and transcriptome sequencing identified RCN3 as a driver of RCC lung metastasis. • RCN3 hypomethylation upregulates its expression and promotes RCC metastasis. • RCN3 binds MMP10 via EF-hand 5–6 domains, enhancing its secretion and PI3K/Akt activation. • Carboxy-pyridostatin 2HCl inhibits metastasis by targeting the RCN3-MMP10 interface.
Lin et al. (Wed,) studied this question.