The translation of a short open reading frame product within the human TUBA1B gene regulates cancer cell proliferation by importin-β

Abstract Understanding cancer biology and the molecular mechanisms underlying cancer progress are crucial for improving cancer treatment strategies. This study revealed a short open reading frame product (sORF1) alternatively translated from the human α-tubulin gene (TUBA1B), which has the completely different amino acids sequence from its main ORF product, α-tubulin 1B chain. sORF1 is highly expressed in cancer cell lines and positive sORF1 cells are found in gastric carcinoma. sORF1 interacts with more than one hundred proteins including importin β. It also acts as a modifier like small ubiquitin-like modifier (SUMO) by covalent binding. Knockdown of sORF1 in cancer cells decreases cell proliferation and tumorigenicity. Further study reveals that the loss of sORF1-importin β connections inhibits importin β guided β-catenin nucleus translocation, thus downregulates Wnt/β-catenin pathway. These findings indicate that gene TUBA1B is a polycistronic gene, able to translate two distinct proteins and the TUBA1B-sORF1 functions as a key tumorigenesis regulator. TUBA1B-sORF1 possesses great potential to be developed as therapeutic target and diagnosis biomarker for cancer.