IRES-mediated translation of Δ160p53 regulates p53 functions and fine-tunes cancer homeostasis

Mutations in p53 and its 12 isoforms can alter its functions. As N-terminally truncated isoforms of p53 (Δ40p53, Δ133p53, and Δ160p53) participate in tetramer formation, they are important regulators of cancer fate. Although Δ40p53- and Δ133p53-mediated regulation of cancer is well reported, the mechanism underlying Δ160p53 production and its functional role remains unclear. We investigated the internal ribosomal entry site (IRES)-mediated translation of Δ160p53 and its role in cancer regulation. As differential synthesis of Δ160p53 was observed under different stress conditions, IRES-mediated translation of this isoform was demonstrated using bicistronic luciferase constructs. No cryptic promoters or splicing sites were detected in the IRES sequence. Cell death and late apoptosis were significantly decreased, while proliferation, the number of cells in the S phase, and drug resistance were induced by Δ160p53. Furthermore, Δ160p53 did not induce p53-responsive promoters. RNA sequencing analysis of Δ160p53 overexpression showed similar results, along with the inhibition of other tumor suppressor genes. Overall, our results provide insights into IRES-mediated translation of Δ160p53, which can be considered a novel target for cancer treatment.