RBM15 promotes lung adenocarcinoma progression and palbociclib sensitivity via m6A-mediated STIL activation and downstream cyclin D1/CDK4 signaling

Abstract

RNA-binding motif protein 15 (RBM15), an N6-methyladenosine (m6A) methyltransferase, plays a crucial role in the progression of lung adenocarcinoma (LUAD); however, the underlying mechanisms remain insufficiently defined. In this study, we investigated the contribution of RBM15-mediated m6A modification to LUAD pathogenesis. Our data showed that RBM15 was highly expressed in LUAD tissues and cell lines. Notably, its expression levels were positively correlated with tumor TNM staging and negatively correlated with differentiation status. The overexpression of RBM15 enhanced cell proliferation, migration, invasion, and cell cycle progression, while simultaneously inhibiting apoptosis. Conversely, RBM15 knockdown reversed these phenotypes and induced G2/M-phase arrest. In vivo experiments further confirmed that RBM15 knockdown led to the suppression of tumor growth. RNA sequencing, MeRIP sequencing, and bioinformatics analyses identified STIL as a gene directly regulated by RBM15 through m6A modification, a finding subsequently validated by luciferase reporter assays. Western blot and rescue experiments demonstrated that RBM15 and STIL cooperatively activate the cyclin D1/CDK4 signaling pathway, thereby promoting LUAD progression. However, this effect was markedly attenuated by CDK4/6 inhibitor application. Collectively, these findings indicated that the RBM15-STIL-cyclin D1/CDK4 axis represents a promising therapeutic target for LUAD.