Regulation of EIF5A and hypusination by p53 determines colorectal cancer cell fitness

Hypusination of eukaryotic translation initiation factor 5 A (EIF5A) by the enzyme deoxyhypusine synthase (DHPS) is a mechanism of regulation of translation that plays a role in cell proliferation. Herein, we assessed the role of hypusination in established colorectal cancer (CRC). Using molecular and biochemical approaches in established CRC cell lines and human colon organoids, we found that the tumor suppressor p53 is a critical regulator of expression of the gene EIF5A1 in the colon, thus supporting EIF5A synthesis and hypusination. Therefore, tissues and cells isolated from patients with CRC harboring TP53 mutation associated with loss of function of p53 exhibited a marked reduction of EIF5A and hypusine level. Further, TP53 mutant CRC cells remained unresponsive to a DHPS inhibitor. However, restoration of wild-type TP53 in these mutated cells supported hypusination-dependent translation of proteins involved in cell growth and rendered them susceptible to DHPS inhibition. Our studies show that loss of EIF5A is an unrecognized molecular feature of TP53 mutation in CRC cells and patients with WT TP53 CRC may benefit from drugs that can inhibit hypusination.