Abstract
Thousands of regulatory non-coding RNAs (ncRNAs) have been annotated, yet their roles in gene regulation and cancer progression remain unclear. Mapping the landscape of ncRNA expression during melanoma progression revealed that ncRNAs represented nearly half of the deregulated genes, with antisense RNAs (asRNAs) comprising a large portion. CDH3-AS1, the most downregulated asRNA, overlaps the CDH3 gene, which encodes P-cadherin, a key cell adhesion protein that is reduced in melanoma. Overexpression of CDH3-AS1 increased cell aggregation and reduced xenograft tumor growth, mimicking the effects of CDH3. CDH3-AS1 interacted with CDH3 mRNA, increased ribosome occupancy, and enhanced P-cadherin translation through a mechanism resembling SINEB2 sequence to up-regulate translation (SINEUP)-mediated translational control. asRNAs complementary to 5' UTRs generally increase the ribosome occupancy of their cognate mRNAs, suggesting broader translational control through this mechanism. This study revealed CDH3-AS1-mediated enhancement of P-cadherin translation as a tumor-suppressive axis in melanoma and highlighted the broader potential of asRNAs as regulators of protein translation.