The translational snapshot of pancreatic cancer reveals sORFs derived microprotein ENEA53 as a novel metabolic regulator interacting with G6PD

Translational control is one process-specific mechanism in tumorigenesis but has been largely neglected. Dysregulated RNAs translation in cancerous cells enable them to rapidly produce specific proteins to drive malignant phenotypes, which is related to transcriptome variations and partially achieved by altering translation efficiency and translating non-canonical sORFs for de novo genes.However, we are just beginning to unravel the translational dysregulations and how the translated non-canonical sORFs function in pancreatic carcinogenesis. Here, through integrated translatome-transcriptome analysis of human pancreatic cancer tissues and cell lines, we identified massive translational dysregulation events, and novel translated sORFs profile. First, we identified abundant RNA variations originating from non-coding regions, which could serve as raw materials for the emergency of new coding sequences. Furthermore, the transcriptional-translational expression decoupling is ubiquitous for the adjustable translational efficiency and potential regulation of translatable uORFs. Additionally, in 2.47% ribosomes associated transcripts derived from the conventional non-coding regions, an extensive sORFs profile including massive non-ATG sORFs were identified. Notably, one novel metabolic regulator-ENEA53, translated from the sORF6 of LINC00511, was proved to interact with G6PD with favorable clinical prospects. We provided a translational snapshot in pancreatic cancer and emphasized the fundamental importance of translational dysregulations, specially the non-canonical sORFs translation in the previously uncharted tumor biology processes, which may contain undefined targets.