DCAF13 promotes hepatocellular carcinoma progression by mediating RCAN1.4 ubiquitination and activating calcineurin/NFAT1 signaling

Hepatocellular carcinoma (HCC) is a malignant tumor with high mortality worldwide. Abnormalities in the ubiquitin proteasome system are considered to contribute to HCC progression. DDB1 and CUL4 associated factor 13 (DCAF13) is a substrate receptor of the E3 ubiquitin ligase CRL4, but its role and downstream substrates in HCC have not been fully elucidated. In this study, we aimed to investigate the regulatory mechanisms of DCAF13 in HCC. Our results demonstrated that DCAF13 was significantly upregulated in HCC tissues and cell lines, and its high expression was correlated with advanced TNM stage and poor overall survival. Functionally, DCAF13 knockdown inhibited HCC cell proliferation, colony formation, and migration, and promoted cell apoptosis in vitro. Knockdown of DCAF13 also suppressed tumor growth in vivo. Through RNA-sequencing, we found that DCAF13 positively regulated the calcium signaling pathway. Mechanistically, we demonstrated that DCAF13 directly binds to RCAN1.4, promotes its ubiquitination and proteasomal degradation. Lower RCAN1.4 levels were associated with a reduction in its inhibitory effect on calcineurin, in which were associated with NFAT1 nuclear accumulation. These findings suggest that DCAF13 promotes HCC progression, at least in part, by facilitating RCAN1.4 ubiquitination and degradation, and contributing to calcium signaling alterations. Accordingly, DCAF13 may serve as a potential biomarker and therapeutical target for HCC.