p53 translational isoform Δ40p53 orchestrates cellular SGSH levels via microRNA-4671-5p to modulate cell cycle

Abstract

ABSTRACTThe translational isoform of full-length p53, Δ40p53, modulates the p53 pathway. We previously showed that Δ40p53 regulates miR-186-5p–YY1 axis, independent of p53, to decrease cell proliferation. In this study, we screened small RNA sequences globally to identify miRNAs differentially regulated by Δ40p53 and p53. We report that the expression of certain miRNAs is exclusively regulated by Δ40p53. Overexpression of Δ40p53, but not full-length p53, substantially downregulated expression of the novel miR-4671-5p. However, upon over expression of different ratios of Δ40p53 and FLp53, miR-4671-5p levels changed which implies that this novel miRNA is not a direct but a p53 modifiable target. Predicted miR-4671-5p targets included N-sulfoglucosamine sulfohydrolase (SGSH), cyclin-dependent kinases(CDK) 11B and CDK5 regulatory subunit 1 (CDK5R1). Overexpression of miR-4671-5p directly inhibited SGSH and consequently triggered intra-S-phase cell cycle arrest. Δ40p53-miR-4671-5p-SGSH axis emerges as a novel axis capable of regulating cell cycle progression. SGSH gene expression levels have potential prognostic relevance on survival that trends in the opposite direction of miR-4671-5p levels associated with the same cancer types, supporting a possible physiological relevance of the interaction. These results enhance understanding of Δ40p53 functions mediated by miRNAs that help to maintain metabolic and cellular homeostasis independently of FLp53.