UBE2J1 inhibits colorectal cancer progression by promoting ubiquitination and degradation of RPS3
Tuo Wang1,2,3,4, Chi Jin1,2,3,4, Peng Yang1,2,3,4
1Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
Abstract:
Ubiquitin-conjugating enzyme E2 J1 (UBE2J1) has been proven to participate in the ubiquitination of multiple substrate proteins. However, the underlying mechanisms of UBE2J1 as a ubiquitin-conjugating enzyme participating in cancer development and progression remain largely unknown. Here, we identified that UBE2J1 is downregulated in colorectal cancer (CRC) tissues and cell lines which are mediated by DNA hypermethylation of its promoter, and decreased UBE2J1 is associated with poor prognosis. Functionally, UBE2J1 serving as a suppressor gene inhibits the proliferation and metastasis of CRC cells. Mechanistically, UBE2J1-TRIM25, forming an E2-E3 complex, physically interacts with and targets RPS3 for ubiquitination and degradation at the K214 residue. The downregulated RPS3 caused by UBE2J1 overexpression restrains NF-κB translocation into the nucleus and therefore inactivates the NF-κB signaling pathway. Our study revealed a novel role of UBE2J1-mediated RPS3 poly-ubiquitination and degradation in disrupting the NF-κB signaling pathway, which may serve as a novel and promising biomarker and therapeutic target for CRC.
Insights
Ubiquitin-conjugating enzyme E2 J1 (UBE2J1) acts as a tumor suppressor in colorectal cancer (CRC). Downregulation of UBE2J1 promotes CRC progression by stabilizing RPS3 and activating the NF-κB pathway.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ubiquitin-conjugating enzyme E2 J1 (UBE2J1) is involved in protein ubiquitination, but its role in cancer remains unclear.
- Understanding UBE2J1's function in colorectal cancer (CRC) is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the role of UBE2J1 in colorectal cancer development and progression.
- To elucidate the molecular mechanisms by which UBE2J1 affects CRC cell behavior.
Main Methods:
- Analysis of UBE2J1 expression in CRC tissues and cell lines.
- Investigation of UBE2J1's effect on CRC cell proliferation and metastasis.
- Identification of UBE2J1's interaction partners and substrates using biochemical assays.
- Examination of the impact of UBE2J1 on the NF-κB signaling pathway.
Main Results:
- UBE2J1 is downregulated in CRC tissues and cell lines due to promoter hypermethylation, correlating with poor prognosis.
- UBE2J1 suppresses CRC cell proliferation and metastasis.
- UBE2J1, via an E2-E3 complex with TRIM25, targets RPS3 for ubiquitination and degradation at K214.
- Downregulation of RPS3 by UBE2J1 inhibits NF-κB nuclear translocation and inactivates the NF-κB pathway.
Conclusions:
- UBE2J1 functions as a tumor suppressor in CRC by promoting RPS3 degradation and inhibiting the NF-κB signaling pathway.
- UBE2J1-mediated regulation of RPS3 and NF-κB offers a potential therapeutic target and biomarker for CRC.
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