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Updated: Jun 3, 2025

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
CDH3-AS1 antisense RNA enhances P-cadherin translation and acts as a tumor suppressor in melanoma
Manon Chadourne1, Crystal Griffith1, Xiaonan Xu1
1Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Abstract:
Thousands of regulatory noncoding RNAs (ncRNAs) have been annotated; however, their functions in gene regulation and contributions to cancer formation remain poorly understood. To gain a better understanding of the influence of ncRNAs on gene regulation during melanoma progression, we mapped the landscape of ncRNAs in melanocytes and melanoma cells. Nearly half of deregulated genes in melanoma are ncRNAs, with antisense RNAs (asRNAs) comprising a large portion of deregulated ncRNAs. CDH3-AS1, the most significantly downregulated asRNA, overlaps the CDH3 gene, which encodes P-cadherin, a transmembrane glycoprotein involved in cell adhesion that was also reduced in melanoma. Overexpression of CDH3-AS1 increased cell aggregation and reduced xenograft tumor growth, mimicking the tumor-suppressive effects of CDH3. CDH3-AS1 interacted with CDH3 mRNA and enhanced P-cadherin protein levels. Interestingly, secondary structures at the CDH3 5' end regulated P-cadherin translation, and ribosome profiling revealed that CDH3-AS1 promotes ribosome occupancy at the CDH3 mRNA. Notably, ribosome occupancy was generally increased in mRNAs having cognate asRNA that are complementary to the 5'UTR. Taken together, this study revealed the CDH3-AS1-mediated enhancement of P-cadherin translation, underscoring the broader potential of asRNAs as regulators of protein-coding genes and their role in diseases like melanoma.
Insights
Antisense RNAs (asRNAs) play a key role in melanoma. CDH3-AS1, an asRNA, enhances P-cadherin translation, suppressing tumor growth and offering new therapeutic targets.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Thousands of regulatory noncoding RNAs (ncRNAs) are known, but their roles in gene regulation and cancer are unclear.
- Melanoma progression involves complex gene regulation, with ncRNAs potentially playing a significant role.
Purpose of the Study:
- To investigate the influence of ncRNAs on gene regulation during melanoma progression.
- To identify specific ncRNAs and their functions in melanoma development.
Main Methods:
- Mapping the landscape of ncRNAs in melanocytes and melanoma cells.
- Analyzing the expression of ncRNAs and their correlation with gene deregulation.
- Investigating the function of CDH3-AS1 through overexpression studies and molecular interaction analyses.
- Utilizing ribosome profiling to understand translational regulation.
Main Results:
- Nearly half of deregulated genes in melanoma are ncRNAs, with antisense RNAs (asRNAs) being a major component.
- CDH3-AS1, a downregulated asRNA, overlaps the CDH3 gene (encoding P-cadherin) and its reduced expression correlates with melanoma.
- Overexpression of CDH3-AS1 suppressed xenograft tumor growth and increased cell aggregation.
- CDH3-AS1 enhances P-cadherin protein levels by promoting ribosome occupancy on CDH3 mRNA, particularly through interactions with the 5' untranslated region.
Conclusions:
- CDH3-AS1 acts as a tumor suppressor in melanoma by enhancing P-cadherin translation.
- Antisense RNAs represent a significant class of gene regulators with potential roles in disease.
- This study highlights the therapeutic potential of targeting asRNA-mediated translational control in melanoma.
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