Inducible tristetraprolin suppresses malignant phenotypes and directly targets glucosaminyl (N-acetyl) transferase 3 in lung cancer cells.

Tristetraprolin (TTP/ZFP36) regulates mRNA expression; however, its target genes in lung cancer remain unclear. Using a CRISPR/Cas9-engineered doxycycline-inducible TTP knock-in model in H460 cells, we investigated the function of TTP in lung cancer cells. Induced TTP expression suppressed clonogenicity, spheroid growth, proliferation, invasion, and migration. Transcriptomic analyses integrated with public lung adenocarcinoma datasets identified glucosaminyl (N-acetyl) transferase 3 (GCNT3) as a key effector of TTP in cancer progression. Mechanistic analyses indicated direct TTP binding to GCNT3, reducing its expression. GCNT3 knockdown attenuated invasion and migration, and GCNT3 re-expression in TTP-induced cells restored and further enhanced these malignant behaviors, establishing a functional relationship between TTP and GCNT3. Transient TTP expression in H1299 cells also reduced GCNT3 levels. These findings identify GCNT3 as a direct TTP target that contributes to malignant behaviors in lung cancer cells, providing insights into post-transcriptional regulation of tumor progression.