Ability of KBTBD10 to inhibit non-small cell lung cancer mediated by LINC01585.

Abstract

Non-small cell lung cancer (NSCLC) imposes a substantial global disease burden. Kelch repeat and BTB domain-containing protein 10 (KBTBD10) constitutes a subunit of E3 ubiquitin ligase complexes and participates in the ubiquitin-proteasome system. Mounting evidence has demonstrated that long non-coding RNAs (lncRNAs) exert critical regulatory effects in NSCLC progression. Herein, we systematically characterized the biological functions and underlying mechanisms of lncRNA LINC01585 and KBTBD10 in NSCLC. We interrogated gene expression patterns using TIMER 2.0 and Kaplan-Meier survival analysis, and further validated KBTBD10 protein expression in clinical NSCLC specimens via immunohistochemistry. Mechanistically, KBTBD10 exerted tumor-suppressive effects in NSCLC by facilitating the ubiquitin-mediated degradation of fused in sarcoma (FUS), whereas FUS upregulated LINC01585 transcription. Clinically, reduced KBTBD10 expression correlated with unfavorable patient survival outcomes. Functionally, LINC01585 promoted the acetylation of cytoplasmic poly(A)-binding protein 1 (PABPC1) and drove oncogenic phenotypes in NSCLC through activation of the signal transducer and activator of transcription 3 (STAT3) signaling cascade. In vitro cellular assays further revealed that LINC01585 boosted interleukin-6 (IL-6) secretion, which establishes a self-amplifying LINC01585/STAT3/IL-6 positive feedback circuit and underscores the vital contribution of the tumor immune microenvironment to NSCLC pathogenesis. Collectively, our study delineates a multilayered regulatory signaling axis linking the immunogenomic microenvironment to NSCLC progression. These results provide mechanistic insights and translational implications for developing immunotherapeutic strategies targeting KBTBD10, and LINC 01585 in NSCLC treatment.