Delta40p53 plays a distinct regulatory role in maintaining cellular homeostasis by controlling SGSH expression via miR-4651-5p

Abstract

{Delta}40p53, the only translational isoform of p53, modulates the full-length p53 (FLp53) activity and independently regulates targets such as the miR-186-5p-YY1 axis. To identify additional miRNAs regulated by {Delta}40p53, we performed small RNA sequencing. We found that overexpression of {Delta}40p53, but not FLp53, significantly downregulated miR-4671-5p. Expression of both isoforms at varying ratios revealed that miR-4671-5p may be modulated by FLp53 in a {Delta}40p53-dependent manner. In silico analysis identified SGSH (N-sulfoglucosamine sulfohydrolase) as a potential miR-4671-5p target. SGSH expression showed inverse correlation with miR-4671-5p in cancer datasets and prognostic significance. SGSH mRNA and protein levels were reduced upon miR-4671-5p overexpression or si{Delta}40p53 treatment, confirming regulatory linkage. Functionally, miR-4671-5p overexpression induced intra-S-phase cell cycle arrest, implicating SGSH in cell cycle regulation. These results reveal a novel {Delta}40p53-miR-4671-5p-SGSH axis that impacts cell cycle progression and may contribute to cancer outcomes. Our findings highlight the distinct regulatory role of {Delta}40p53, independent of FLp53, in maintaining cellular and metabolic homeostasis via miRNA-mediated mechanisms.