Chen Jingyi, Fan Chongyu, Song Songze, Zhang Deyu
Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China.
Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
Cell Death Dis. 2025 Aug 11;16(1):607. doi: 10.1038/s41419-025-07931-3.
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.
非小细胞肺癌（NSCLC）是最常见的恶性肿瘤类型之一，其特点是转移率和死亡率高。然而，NSCLC生长和进展的分子机制仍 largely不清楚。在此，EP300-AS1被鉴定为NSCLC中一种关键的肿瘤抑制性长链非编码RNA（lncRNA）。EP300-AS1在体外和体内均抑制NSCLC细胞的生长和转移，并与更好的临床结果相关。EP300-AS1的功能取决于EP300-AS1与PTBP1的相互作用以及PTBP1介导的PRMT5 mRNA稳定性。EP300-AS1直接与PTBP1结合，阻止其在NSCLC中的细胞质易位以及PTBP1-PRMT5 mRNA复合物的形成。在没有PTBP1与PRMT5 mRNA 3'-UTR结合的情况下，PRMT5 mRNA的稳定性和表达会降低。敲低PTBP1或抑制PRMT5可消除EP300-AS1调节的NSCLC细胞增殖、迁移和侵袭。在肺腺癌（LUAD）和肺鳞状细胞癌（LUSC）患者中，EP300-AS1表达与PRMT5表达呈负相关。总体而言，这些发现确立了EP300-AS1-PTBP1-PRMT5轴作为NSCLC进展中的关键调节途径，为NSCLC的预测和治疗提供了一种新的调节机制和有前景的靶点。
