m1A methylation-mediated upregulation of RILsPL1 promotes colorectal cancer progression via the CaMKII/CREB signaling pathway.

Colorectal cancer (CRC) remains one of the most lethal malignancies globally, driven by complex molecular mechanisms that contribute to its progression and metastasis. This study focuses on the role of N1-methyladenosine (mA) RNA methylation in CRC, particularly its effect on Rab Interacting Lysosomal Protein-Like 1 (RILPL1) expression and the downstream activation of the CaMKII/CREB signaling pathway. Bioinformatics analysis identified RILPL1 as a key gene associated with poor CRC prognosis, exhibiting increased expression levels in cancerous tissues, with further elevation in metastatic samples. Functional assays demonstrated that mA methylation enhances the stability of RILPL1 mRNA, a process dynamically regulated by the opposing actions of the demethylase ALKBH1 and the methyltransferase TRMT6. Loss-of-function and gain-of-function studies showed that RILPL1 promotes CRC cell viability, invasion, and migration, highlighting its oncogenic role. In vivo, RILPL1 knockdown markedly suppressed tumor growth in a nude mouse xenograft model. Furthermore, the CaMKII/CREB signaling pathway was identified as a critical mediator, with RILPL1 expression levels directly correlating with the phosphorylation of CaMKII and CREB both in vitro and in vivo xenograft models. Pharmacological rescue experiments confirmed this dependency, as a CaMKII activator reversed the effects of RILPL1 knockdown, while a specific inhibitor blocked this rescue. These findings suggest that dynamic mA methylation-driven upregulation of RILPL1 contributes to CRC progression through the activation of the CaMKII/CREB signaling pathway, offering potential therapeutic targets for CRC treatment.