M6A -mediated lncRNA SCIRT stability promotes NSCLC progression through binding to SFPQ and activating the PI3K/Akt pathway.

Abstract

Non-small cell lung cancer (NSCLC) has emerged as one of the most prevalent malignancies worldwide. N6-methyladenosine (m⁶A) methylation, a pervasive epigenetic modification in long noncoding RNAs (lncRNAs), plays a crucial role in NSCLC progression. Here, we report that m⁶A modification and the expression of the lncRNA stem cell inhibitory RNA transcript (SCIRT) was significantly upregulated in NSCLC tissues and cells. Functional analysis revealed that SCIRT enhanced NSCLC cell proliferation, migration, invasion, and epithelial‒mesenchymal transition. The m⁶A modification of SCIRT can be installed by METTL3, which enhanced the stability of this lncRNA. Notably, SCIRT overexpression in response to DNA double-strand breaks (DSBs) sensitized cells to camptothecin (CPT) and impairs DNA homologous recombination repair. SCIRT directly interacted with SFPQ in vitro and was primarily localized in the nucleus. Furthermore, ectopic SCIRT expression upregulated SFPQ and activated the PI3K/Akt pathway following CPT treatment, suggesting an unexpected role of SCIRT in facilitating SFPQ-mediated DSB repair. In brief, our findings highlight the oncogenic role of SCIRT in NSCLC by binding SFPQ and activating PI3K/Akt signaling, presenting a promising therapeutic target for personalized NSCLC treatment.