GALNT4 promotes the stemness of non-small cell lung cancer through O-glycosylation of MUC5AC via ITGB4/PI3K/AKT signaling pathway.

Cancer stem cells (CSCs) are regarded as the fundamental cause of cancer occurrence, development, and recurrence. The O-Glycosylation catalyzed by polypeptide N-acetylgalactosamine (GalNAc) transferase family (GALNTs) exerts a crucial effect on non-small cell lung cancer (NSCLC) progression. In this study, lung cancer stem cells (LCSCs) exhibited stronger abilities for proliferation and apoptosis resistance. The expression profiles of 20 GALNTs were different comparing NSCLC cell lines with LCSCs, whereas LCSCs exhibited higher expression of GALNT4. Functionally, alteration of GALNT4 in LCSCs modulated malignant behaviors both in vitro and in vivo. GALNT4 was directly involved in the O-glycosylation of MUC5AC and activated the PI3K/AKT pathway. KLF5 regulated by GALNT4 recruited P300 to form a transcription complex, which effectively mediated the transcription and translation of MUC5AC and ITGB4. Moreover, GALNT4/MUC5AC/ITGB4 crosstalk modified the stem cell characteristics of LCSCs. Overall, the regulatory GALNT4/KLF5/P300 crosstalk promoted the stemness maintenance in LCSCs through O-glycosylation of MUC5AC and activation of the ITGB4/PI3K/AKT signaling pathway. This study might provide potential new targets and strategies for NSCLC treatment.