Abstract

Cancer stemness is a critical determinant of tumor progression and poor prognosis in non–small cell lung cancer (NSCLC), however, the mechanisms by how long noncoding RNAs (lncRNAs) regulate stemness-associated signaling pathways remain incompletely understood. Here, we identify long-intergenic non-coding RNA for kinase activation (LINK-A) as a key regulator of NSCLC stemness that is markedly upregulated in tumor tissues and serum. Functional analyses demonstrate that LINK-A enhances cancer stem-like properties and accelerates tumor growth in vivo. Mechanistically, LINK-A predominantly localizes to the cytoplasm, where it binds to the RNA-binding protein heterogeneous nuclear ribonucleoprotein K (hnRNPK) and promotes its cytoplasmic retention. Cytoplasmic hnRNPK associates with beta-catenin (β-catenin) and the deubiquitinase ubiquitin carboxyl-terminal hydrolase 9× (USP9X), preventing β-catenin ubiquitination and subsequently enhancing Wnt/β-catenin signaling. This activation induces the transcription of Nanog homeobox (NANOG) and POU class 5 homeobox 1 (POU5F1/OCT4), thereby sustaining NSCLC stemness. Collectively, these findings identify a previously unrecognized LINK-A/hnRNPK/USP9X/β-catenin signaling axis and highlight LINK-A as a potential biomarker and therapeutic target for NSCLC.