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Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors in the urinary system, and its incidence continues to increase. Regulator of calcineurin 1 (RCAN1), one of the genes on chromosome 21, is a crucial mediator of tumor inhibition. RCAN1.4 is best characterized as an endogenous inhibitor of the phosphatase calcineurin, and it has been observed to be downregulated in numerous types of cancer. However, its essential function remains unclear in ccRCC. In the present study, we found that RCAN1.4 expression was frequently downregulated in renal cell carcinoma tissues and cells and was inversely correlated with various clinicopathological parameters. Low RCAN1.4 expression was associated with poor overall survival and disease-free survival and could act as a diagnostic indicator in ccRCC patients. Furthermore, the overexpression of RCAN1.4 inhibited cell proliferation, migration and invasion, whereas RCAN1.4 knockdown promoted these functions in ccRCC cell lines. In addition, RCAN1.4 expression was downregulated in sunitinib-resistant renal cancer cell lines, and inhibition of RCAN1.4 promoted sunitinib resistance. We also found that RCAN1.4 could regulate epithelial-mesenchymal transition (EMT) and the expression of HIF2α in sunitinib-resistant cell lines. Taken together, these findings indicate that downregulation of RCAN1.4 may be crucial for the metastasis of ccRCC and may induce sunitinib resistance. RCAN1.4 may act as a prognostic indicator and potential therapeutic target for ccRCC.