Disruption of the ∆40p53/miR-4671-5p/SGSH axis results in intra-S-phase arrest and poor cancer prognosis.

Parsing the functions of the tumor suppressor tumor protein p53 (TP53) is complex due to the multiple isoforms it encodes. ∆40p53, an N-terminally truncated p53 isoform and the only translational isoform, modulates full-length p53 (FLp53) activity and independently regulates targets such as the miR-186-5p/transcriptional repressor protein YY1 axis. To identify additional miRNAs regulated by ∆40p53, we performed small RNA sequencing. We found that ectopic overexpression of ∆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 ∆40p53-dependent manner. In silico analysis identified N-sulfoglucosamine sulfohydrolase (SGSH) as a potential miR-4671-5p target. SGSH expression showed an inverse correlation with miR-4671-5p in cancer datasets and had prognostic significance. SGSH mRNA and protein levels were reduced upon miR-4671-5p overexpression or si∆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 previously unknown ∆40p53/miR-4671-5p/SGSH axis that, when dysregulated, induces intra-S-phase cell cycle arrest and may contribute to cancer outcomes. Our findings highlight the distinct regulatory role of ∆40p53, independent of FLp53, in maintaining cellular and metabolic homeostasis via miRNA-mediated mechanisms.