Abstract

Non-small-cell lung cancer (NSCLC) is one of the most common types of malignant cancer, characterized by high rates of metastasis and mortality. However, the molecular mechanisms underlying NSCLC growth and progression remain largely unclear. Here, EP300-AS1 is identified as a critical tumor-suppressive long non-coding RNA (lncRNA) in NSCLC. EP300-AS1 inhibits NSCLC cell growth and metastasis both in vitro and in vivo, and is associated with better clinical outcomes. The function of EP300-AS1 depends on EP300-AS1-PTBP1 interaction and PTBP1-mediated PRMT5 mRNA stability. EP300-AS1 binds directly to PTBP1, preventing its cytoplasmic translocation and PTBP1-PRMT5 mRNA complex formation in NSCLC. In the absence of PTBP1 binding to the PRMT5 mRNA 3'-UTR, PRMT5 mRNA stability and expression are reduced. PTBP1 knockdown or PRMT5 inhibition abolishes EP300-AS1-regulated NSCLC cell proliferation, migration, and invasion. In patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), EP300-AS1 expression is negatively correlated with PRMT5 expression. Overall, these findings establish the EP300-AS1-PTBP1-PRMT5 axis as a key regulatory pathway in NSCLC progression, providing a novel regulatory mechanism and a promising target for NSCLC prediction and therapy.