Long noncoding RNA MNX1-AS1 mediated regulation of one-carbon metabolism by preventing CACYBP degradation to promote lung cancer progression

Lung cancer remains the leading cause of cancer-related death worldwide, and long noncoding RNAs (lncRNAs) have been implicated in its tumourigenesis and progression. However, the roles lncRNAs play in lung cancer remain unclear. In this study, we discovered an important role for the lncRNA MNX1 Antisense RNA 1 (MNX1-AS1) as a critical regulator of one-carbon metabolism reprogramming. Glutamine depletion altered chromatin accessibility, leading to downregulation of MNX1-AS1, while elevated expression of MNX1-AS1 was correlated with poor prognosis in patients with non-small cell lung cancer. Functional studies showed that MNX1-AS1 promoted cell proliferation and sphere formation in vitro, and subcutaneous and orthotopic tumour growth in vivo. Mechanistically, MNX1-AS1 directly binds to calcyclin binding protein (CACYBP), protecting it from ubiquitin-mediated degradation; thus, the MNX1-AS1/CACYBP complex accelerates the transcription of key one-carbon metabolism-related genes through the Wnt/β-catenin pathway. MNX1-AS1/CACYBP/β-catenin axis upregulated key one-carbon metabolism-related genes, which were essential for generating related metabolites and maintaining cellular redox balance to support lung cancer cell proliferation. These findings established that the lncRNA MNX1-AS1 acts as a crucial driver of one-carbon metabolism reprogramming in non-small cell lung cancer and highlight that the newly identified MNX1-AS1/CACYBP/β-catenin axis may serve as a potential prognostic biomarker and therapeutic target for lung cancer intervention.