Long noncoding RNAs (lncRNAs) have attracted considerable attention for their roles as either oncogenes or tumor suppressors in cancer development. Yet, the specific functions and molecular mechanisms of the majority of lncRNAs in colorectal cancer (CRC) remain poorly understood. DLGAP1-AS2 levels were quantified using RT-qPCR across several CRC patient cohorts. Its effects on CRC cell proliferation and metastatic potential were investigated through a combination of in vitro and in vivo assays. The molecular interactions and regulatory mechanisms of DLGAP1-AS2 were explored using RNA pull-down, RNA immunoprecipitation, RNA sequencing, luciferase reporter assays, chromatin immunoprecipitation, and rescue experiments. DLGAP1-AS2 was found to enhance CRC tumor growth and metastasis by binding directly to Elongin A (ELOA) and reducing its stability via Trim21-mediated ubiquitination and subsequent degradation. Furthermore, DLGAP1-AS2 suppresses LHPP expression by interfering with ELOA-driven transcriptional activation, thereby preventing LHPP-dependent inhibition of the AKT pathway. In addition, cleavage and polyadenylation factors CPSF2 and CSTF3 were shown to interact with DLGAP1-AS2, stabilizing it in CRC cells. DLGAP1-AS2 represents a novel prognostic marker and offers insight into the molecular drivers of CRC, highlighting a potential target for therapeutic intervention.
