The “LINC” in between Δ40p53-miRNA axis in the regulation of cellular homeostasis

ABSTRACT Previous research has shown that Δ40p53, the translational isoform of p53, can inhibit cell growth independently of p53 by regulating microRNAs. Here, we explored the role of Δ40p53 in regulating the long non-coding RNA-microRNA-cellular process axis, specifically focusing on LINC00176. Interestingly, LINC00176 levels were predominantly affected by the overexpression/stress-mediated induction and knockdown of Δ40p53 rather than p53 levels. Additional assays revealed that Δ40p53 transactivates LINC00176 transcriptionally and could also regulate its stability. RNA immunoprecipitation experiments revealed that LINC00176 sequesters several putative microRNA targets, which could further titrate several mRNA targets involved in different cellular processes. To understand the downstream effects of this regulation, we ectopically overexpressed and knocked down LINC00176 in HCT116 p53−/− (harboring only Δ40p53) cells, which affected their proliferation, cell viability, and expression of epithelial markers. Our results provide essential insights into the pivotal role of Δ40p53 in regulating the novel LINC00176 RNA-microRNA-mRNA axis independent of FL-p53 and in maintaining cellular homeostasis.