Histidine to glutamine substitutants, a regulated process that impacts cell survival and suggests histidine shortage in cancer.

Cancer-associated genetic, epigenetic, and microenvironmental factors impose shortages of tryptophan and arginine, which induce specific codon reassignments (substitutants) in their proteomes. Whether cancers are deprived of other amino acids is unknown. Histidine is an essential amino acid reported to be low in certain tumor types. Therefore, we investigated the potential for a histidine shortage in cancer. Using cultured cancer cells, we pinpointed histidine to glutamine (H>Q) substitutants as the most pronounced proteomic event following histidine deprivation. We then scanned cancer proteomes for H>Q proteins and observed a marked enrichment in pancreatic, uterine, and kidney cancers. Mechanistically, we propose that H>Q is a result of tRNA misalignment, and used tRNA glutamine (tRNA(Gln)) modifications at the wobble position to demonstrate it. We further show that URM1-mediated U34 thiolation boosts H>Q production and influences the survival of cancer cells following histidine deprivation, suggesting a potential role for H>Q. Additional characterization of H>Q substitutants revealed preferred sequences and the maintenance of H>Q host protein expression despite the absence of histidine, indicating cellular regulation and functional consequences. Thus, histidine shortage induces H>Q substitutants, a regulated mistranslation event that pinpoints histidine limitation in cancer and impacts cell survival.