m6A-mediated DGUOK-AS1 stabilized by RBM15 and HNRNPH1 promotes lung adenocarcinoma progression

Abstract Background: LncRNAs play pivotal roles in the development and progression of various cancers. This study aimed to investigate the regulatory mechanism of the lncRNA DGUOK-AS1 expression in LUAD，and to evaluate its value in lung cancer diagnosis. Methods: We dectectd the DGUOK-AS1 expression levels in clinical serum samples and its cellular localization in LUAD by using RT-qPCR and FISH. The changes in proliferation and migration were analyzed both in vitro and in vivo. Dual-luciferase reporter gene assays and RIP-qPCR were used to explore the DGUOK-AS1/miR-2467-5p/PRMT5 aixs. Additionally, RIP and RNA pull-down assays confirmed the interaction between RBPs and DGUOK-AS1. MeRIP-qPCR was conducted to verify the regulatory function of RBM15 in DGUOK-AS1 m⁶A modification and expression. Actinomycin D treatment was employed to investigate the influence of RBM15 and HNRNPH1 on DGUOK-AS1 stability and expression. Results: DGUOK-AS1 was high expression in lung adenocarcinoma (LUAD) and may serve as potential diagnostic biomarkers for lung cancer. DGUOK-AS1 enhanced the upregulation of its target PRMT5 by acting as a sponge for miR-2467-5p in the cytoplasm, thereby promoting LUAD progression both in vitro and in vivo. Mechanistically, RBM15 interacted with DGUOK-AS1 and the RBM15-mediated m⁶A modification contributed to the stability of DGUOK-AS1 in the nucleus. Functionally, RBM15 knockdown reduced the expression of DGUOK-AS1, thereby inhibiting the proliferation and migration of LUAD cells via miR-2467-5p/PRMT5 axis. Additionally, the RRM3 domain of HNRNPH1 interacted with DGUOK-AS1 and facilitated its degradation, thereby regulated its expression. Conclusion: We concluded that RBM15 and HNRNPH1 increase the stability and expression of DGUOK-AS1, and promote LUAD progression through the miR-2467-5p/PRMT5 axis. This study identified DGUOK-AS1 as a critical regulator of LUAD progression and this provides a potential therapeutic target for LUAD.