The m6A reader IGF2BP1 manipulates BUB1B expression to affect malignant behaviors, stem cell properties, and immune resistance of non-small-cell lung cancer stem cells.

Abstract

N6-methyladenosine (m6A) modification is the most common internal modification in eukaryotic mRNA and an important mechanism for post-transcriptional regulation of genes. This study focuses on the role of the m6A reader insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) in the malignant behaviors of non-small-cell lung cancer (NSCLC) cells and especially the cancer stem cells (CSCs). We obtained IGF2BP1 as an aberrantly upregulated gene linking to poor survival of patients with NSCLC by bioinformatics, and then confirmed increased IGF2BP1 expression in NSCLC tissues and cells, especially in the enriched CSCs. Knockdown of IGF2BP1 suppressed proliferation, mobility and epithelial-mesenchymal transition activity of NSCLC cells and CSCs, and it reduced stemness, self-renewal ability, xenograft tumorigenesis and immune resistance of the CSCs. IGF2BP1 was predicted to have a positive correlation with BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B), and it upregulated BUB1B expression through m6A modification. Further overexpression of BUB1B in CSCs counteracted the effects of IGF2BP1 silencing and restored the malignant phenotype, self-renewal, and immune resistance of CSCs in vitro and in vivo. Taken together, this work demonstrates that IGF2BP1 manipulates BUB1B expression to affect malignant behaviors, stem cell properties and immune resistance of NSCLC stem cells.