Guo Yanru, Xing Ruotong, Li Qianyi, Zhou Wanting, Qi Xia, Li Shijun
Department of Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province 116011, China; College of Laboratory Medicine, Dalian Medical University, Dalian, Liaoning Province 116044, China.
Department of Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province 116011, China.
Cell Signal. 2025 Oct;134:111934. doi: 10.1016/j.cellsig.2025.111934. Epub 2025 Jun 10.
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.
癌症干细胞（CSCs）被认为是癌症发生、发展和复发的根本原因。由多肽N-乙酰半乳糖胺（GalNAc）转移酶家族（GALNTs）催化的O-糖基化对非小细胞肺癌（NSCLC）的进展发挥着关键作用。在本研究中，肺癌干细胞（LCSCs）表现出更强的增殖和抗凋亡能力。与LCSCs相比，NSCLC细胞系中20种GALNTs的表达谱不同，而LCSCs表现出更高的GALNT4表达。在功能上，LCSCs中GALNT4的改变在体外和体内均调节恶性行为。GALNT4直接参与MUC5AC的O-糖基化并激活PI3K/AKT途径。受GALNT4调控的KLF5招募P300形成转录复合物，该复合物有效地介导了MUC5AC和ITGB4的转录和翻译。此外，GALNT4/MUC5AC/ITGB4的相互作用改变了LCSCs的干细胞特征。总体而言，调控性的GALNT4/KLF5/P300相互作用通过MUC5AC的O-糖基化和ITGB4/PI3K/AKT信号通路的激活促进了LCSCs干性的维持。本研究可能为NSCLC治疗提供潜在的新靶点和策略。
