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Published on: January 22, 2013
NEDD4L Suppresses Proliferation and Promotes Apoptosis by Ubiquitinating RAC2 Expression and Acts as a Prognostic
Manlong Qi1, Jianqiao Tu1, Rong He1
1Department of Clinical Genetics, The Affiliated Shengjing Hospital, China Medical University, Shenyang 110004, China.
Abstract:
Neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) is an HECT (homologous to E6AP C terminus)-type E3 ubiquitin ligase. As previously documented, bioinformatics analysis revealed NEDD4L is downregulated in clear cell renal cell carcinoma (ccRCC). However, the target substrate regulated by NEDD4L in ccRCC remains unknown. Here, we assessed whether NEDD4L regulates Ras-related C3 botulinum toxin substrate 2 (RAC2) expression in ccRCC. In our study, integrated bioinformatics analysis indicated that low expression of NEDD4L and high expression of RAC2 were both associated with poor prognosis of ccRCC, pro-tumorigenic immunity, and multiple tumor-associated pathways. Our data confirmed the hypothesis indicated in the previous studies related to the downregulation of NEDD4L in ccRCC. NEDD4L was identified to target the RAC2 threonine 108-proline motif, and RAC2 overexpression rescued NEDD4L-mediated cell apoptosis and inhibition of cell growth and migration. Therefore, RAC2 is a novel and first identified target of NEDD4L in ccRCC, and the aberrant less expression of NEDD4L and consequent RAC2 upregulation may contribute to renal carcinogenesis. Our study offers insight into NEDD4L as a potential future therapeutic target for renal cell carcinoma or as a novel prognostic biomarker.
Insights
Neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) is downregulated in clear cell renal cell carcinoma (ccRCC). We identified RAC2 as NEDD4L’s target, suggesting NEDD4L’s role in ccRCC progression and potential as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L) is an E3 ubiquitin ligase.
- NEDD4L is known to be downregulated in clear cell renal cell carcinoma (ccRCC).
- The specific substrate targeted by NEDD4L in ccRCC has remained unidentified.
Purpose of the Study:
- To investigate whether NEDD4L regulates Ras-related C3 botulinum toxin substrate 2 (RAC2) expression in ccRCC.
- To explore the functional consequences of NEDD4L-RAC2 interaction in ccRCC pathogenesis.
- To evaluate NEDD4L and RAC2 as potential biomarkers or therapeutic targets in ccRCC.
Main Methods:
- Integrated bioinformatics analysis of ccRCC patient data.
- Experimental validation of NEDD4L-RAC2 interaction.
- Assessment of cell apoptosis, growth, and migration following manipulation of NEDD4L and RAC2 expression.
Main Results:
- Low NEDD4L and high RAC2 expression correlate with poor ccRCC prognosis, immune infiltration, and oncogenic pathways.
- NEDD4L directly targets RAC2 at the threonine 108-proline motif.
- RAC2 overexpression rescues NEDD4L-mediated inhibition of ccRCC cell apoptosis, growth, and migration.
Conclusions:
- RAC2 is identified as the first direct target of NEDD4L in ccRCC.
- Aberrant downregulation of NEDD4L and subsequent RAC2 upregulation likely contribute to renal carcinogenesis.
- NEDD4L presents potential as a prognostic biomarker and therapeutic target for ccRCC.
