Human TUBA1B short open reading frame product regulates cancer cell growth via importin-β

Understanding cancer biology is crucial for improving treatment strategies. This study identified TUBA1B-sORF1, a short open reading frame product alternatively translated from the human -tubulin gene (TUBA1B), which has a completely different amino acid sequence from the -tubulin 1B chain. TUBA1B-sORF1 is highly expressed in cancer cell lines and gastric carcinoma. Both methionine-initiated canonical and leucine-initiated noncanonical translations of TUBA1B-sORF1 coexist in cancer cells, and there is a transition between sORF1 and -tubulin translations, evidenced by the TUBA1B-sORF1/-tubulinlow/- subpopulation. Knocking down TUBA1B-sORF1 reduces cancer cell proliferation and tumorigenicity. TUBA1B-sORF1 facilitates protein nuclear translocation, leading to the upregulation of proliferation-promoting genes and downregulation of proliferation-inhibiting genes. Specifically, it forms a complex with importin {beta} and {beta}-catenin, promoting {beta}-catenin nuclear translocation and target gene transcription. These findings reveal that TUBA1B is a polycistronic gene translating at least two entirely different proteins: -tubulin and TUBA1B-sORF1. The variable translation between them may regulate tumorigenesis, making TUBA1B-sORF1 a promising therapeutic target and diagnostic biomarker for cancer treatment.