Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Department of Oncology, The Affiliated Xinyu Hospital, Nanchang University, Xinyu, China.
J Cell Mol Med. 2021 May;25(9):4275-4286. doi: 10.1111/jcmm.16480. Epub 2021 Apr 8.
Long non-coding RNAs (lncRNAs) are a novel class of regulators in multiple cancer biological processes. However, the functions of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. In this study, we identified PWAR6 as a frequently down-regulated lncRNA in PDAC samples as well as a panel of pancreatic cancer cell lines. Down-regulated PWAR6 was associated with multiple clinical outcomes, including advanced tumour stage, distant metastasis, and overall survival of PDAC patients. In our cell-based assays, ectopic expression of PWAR6 dramatically repressed PDAC cells proliferation, invasion and migration, accelerated apoptosis, and induced cell cycle arrest at G0/G1 phase. In contrast, depletion of PWAR6 mediated by siRNA exhibited opposite effects on PDAC cell behaviours. In vivo study further validated the anti-tumour role of PWAR6 in PDAC. By taking advantage of available online sources, we also identified YAP1 as a potential PWAR6 target gene. Negative correlation between YAP1 and PWAR6 expressions were observed in both online database and our PDAC samples. Notably, rescue experiments further indicated that YAP1 is an important downstream effector involved in PWAR6-mediated functions. Mechanistically, PWAR6 could bind to methyltransferase EZH2, a core component of Polycomb Repressive Complex 2 (PRC2) in regulating gene expression, and scaffold EZH2 to the promoter region of YAP1, resulting in epigenetic repression of YAP1. In conclusion, our data manifest the vital roles of PWAR6 in PDAC tumorigenesis and underscore the potential of PWAR6 as a promising target for PDAC diagnosis and therapy.
长链非编码 RNA（lncRNAs）是多种癌症生物学过程中的新型调控因子。然而，lncRNAs 在胰腺导管腺癌（PDAC）中的功能仍知之甚少。在本研究中，我们鉴定了 PWAR6 是 PDAC 样本以及一系列胰腺癌细胞系中频繁下调的 lncRNA。下调的 PWAR6 与多种临床结局相关，包括肿瘤晚期、远处转移和 PDAC 患者的总生存期。在我们的细胞实验中，PWAR6 的异位表达显著抑制 PDAC 细胞的增殖、侵袭和迁移，加速细胞凋亡，并诱导细胞周期停滞在 G0/G1 期。相反，通过 siRNA 耗竭 PWAR6 则对 PDAC 细胞行为表现出相反的作用。体内研究进一步验证了 PWAR6 在 PDAC 中的抗肿瘤作用。通过利用现有在线资源，我们还鉴定了 YAP1 是 PWAR6 的潜在靶基因。在在线数据库和我们的 PDAC 样本中均观察到 YAP1 和 PWAR6 表达之间的负相关。值得注意的是，挽救实验进一步表明 YAP1 是参与 PWAR6 介导的功能的重要下游效应子。在机制上，PWAR6 可以与甲基转移酶 EZH2 结合，EZH2 是多梳抑制复合物 2（PRC2）的核心组成部分，调节基因表达，并将 EZH2 支架到 YAP1 的启动子区域，导致 YAP1 的表观遗传抑制。总之，我们的数据表明 PWAR6 在 PDAC 肿瘤发生中具有重要作用，并强调了 PWAR6 作为 PDAC 诊断和治疗有前途的靶点的潜力。
