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Published on: April 11, 2025
RNF187 neddylation in pancreatic cancer activates malignancy via IQGAP1-dependent actin cytoskeleton rearrangement
Chengxiao Yang1,2,3, Xinyuan Liu2,3, Wenbo Yang1,2
1Department of Hepatobiliary and Pancreas Surgery, Qunli District, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Abstract:
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.
Insights
Neddylation stabilizes RNF187, promoting pancreatic cancer (PC) cell growth and invasion. RNF187 further boosts PC malignancy by upregulating IQGAP1 and MYH9, offering a potential therapeutic target for pancreatic cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Neddylation is a key post-translational modification in cancer.
- Its role in pancreatic cancer (PC) pathogenesis is not well understood.
- Identifying novel regulators of PC is crucial for therapeutic development.
Purpose of the Study:
- To investigate the role of neddylation-related molecules in pancreatic cancer.
- To identify key molecules involved in PC progression.
- To elucidate the molecular mechanisms by which RNF187 promotes PC malignancy.
Main Methods:
- Screening of neddylation-related molecules in PC.
- In vitro and in vivo assays to assess cell proliferation and invasion.
- Ubiquitination assays to analyze protein degradation pathways.
- Western blotting and qRT-PCR to measure protein and gene expression levels.
Main Results:
- RNF187 was identified as significantly overexpressed in PC tissues and cell lines.
- NEDD8 binding to RNF187 inhibited its degradation, increasing RNF187 protein levels.
- RNF187 overexpression enhanced PC cell proliferation and invasion.
- RNF187 upregulated IQGAP1 and MYH9, promoting actin cytoskeleton rearrangement and PC malignancy.
Conclusions:
- Neddylation of RNF187 enhances pancreatic cancer malignancy.
- The IQGAP1/MYH9 signaling axis is critical for RNF187-mediated PC progression.
- RNF187 represents a promising therapeutic target for pancreatic cancer treatment.
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