KEY TAKEAWAYS
- The study aimed to assess the differential expression of UBC12 and NEDD8 among PTX-sensitive and PTX-insensitive TNBC tissues.
- The neddylation downregulation with PTX treatment demonstrated enhanced tumor suppression in TNBC.
In the poor prognosis of triple-negative breast cancer (TNBC), Paclitaxel (PTX) treatment resistance is a considerable factor. There is a need to identify new targets for designing therapeutic combinations for the treatment. Neddylation is a post-translational process that introduces a ubiquitin-like protein called neural precursor cell expressed developmentally downregulated protein 8 (NEDD8).
Past studies have established that neddylation is activated in various tumor conditions but its association with PTX chemotherapy sensitivity has yet to be reported.
Bowen Zheng and the team investigated the differences in UBC12 and NEDD8 expression levels between PTX-sensitive and PTX-insensitive TNBC.
Researchers conducted a differential expression analysis, to confirm variations in UBC12 and NEDD8 expression levels among PTX-sensitive and PTX-insensitive TNBC tissues samples, that were further validated through public databases and immunohistochemistry.
In vitro and in vivo functional experiments were employed to assess the impact of neddylation inhibition combined with PTX therapy on tumor progression. Molecular mechanisms were investigated using Co-IP, western blot, and PCR assays.
Molecular docking simulated the protein binding interactions of UBC12 with tripartite motif containing 25 (TRIM25), while molecular dynamics (MD) simulations observed changes in TRIM25 protein conformation.
Results revealed that in PTX-insensitive TNBC samples, there was an increased expression of NEDD8 and its conjugating enzyme UBC12. Treatment with the NEDD8-activating enzyme (NAE) inhibitor mln4924 or knockdown of UBC12 significantly increased tumor sensitivity to PTX. This increased sensitivity was linked to UBC12-mediated activation of autophagy. Mechanistically, UBC12 transfers NEDD8 to the E3 ubiquitin ligase TRIM25 at K117.
MD simulations indicated that neddylation modification of TRIM25 alleviates steric hindrance in its RING domain, facilitating TRIM25’s binding to ubiquitylated substrates.
Subsequently, TRIM25 promotes nuclear translocation of transcription factor EB (TFEB) and transcription of autophagy-related genes through increased K63-polyubiquitination of TFEB, thereby reducing tumor sensitivity to PTX.
The study concluded that neddylation is enhanced in PTX-insensitive TNBC. In particular, autophagy gene transcriptional activation mediated by the UBC12/TRIM25/TFEB axis reduced TNBC sensitivity to PTX. Downregulation of neddylation in combination with PTX treatment showed a synergistic effect in tumor suppression.
The study was supported by grants from the National Natural Science Foundation of China (no. 82073204), the Shanghai Municipal Health Commission (no. 202040157), and the Shanghai Tenth People’s Hospital (No. YNCR2B008).
Source: https://pubmed.ncbi.nlm.nih.gov/38926803/
Zheng B., Qian F., Wang X., et al. (2024). “Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy.” J Exp Clin Cancer Res. 2024 Jun 26;43(1):177. doi: 10.1186/s13046-024-03085-w. PMID: 38926803.
