RNF187 neddylation in pancreatic cancer activates malignancy via IQGAP1-dependent actin cytoskeleton rearrangement.

Neddylation, a post-translational modification process involving three enzymatic steps, is crucial in regulating various cancers. However, its specific mechanisms in pancreatic cancer (PC) remain largely unexplored. This study focused on screening neddylation-related molecules in PC and identified RNF187 as a key player, demonstrating its overexpression in PC and its ability to enhance cell proliferation and invasion both in vitro and in vivo. Notably, NEDD8 could bind to RNF187, preventing its degradation via K48-linked ubiquitination. This interaction stabilized RNF187, leading to increased protein levels and subsequent stimulation of PC cell proliferation and invasion. However, this mechanism alone did not fully account for how RNF187 could exacerbate PC malignancy. Further research revealed that RNF187 upregulated IQGAP1 protein levels through modulation of K48- and K63-linked ubiquitination. This post-translational modification triggered the rearrangement of the actin cytoskeleton in PC cells by altering the transcriptional levels of MYH9, thereby promoting PC malignancy. Overall, our findings demonstrate that neddylation of RNF187 enhances PC malignancy through the IQGAP1/MYH9 axis, suggesting a new therapeutic target for PC.