Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
Department of Breast Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yudong Road, Yantai, Shandong 264001, P.R. China.
Theranostics. 2021 Mar 4;11(9):4516-4530. doi: 10.7150/thno.54549. eCollection 2021.
Accumulating evidence indicates that long noncoding RNAs (lncRNAs) play crucial roles in cancer progression; however, only few have been characterized in detail. The current study aimed to identify a novel cancer driver lncRNA in glioblastoma and colon adenocarcinoma. We performed whole transcriptome analysis of TCGA pan-cancer datasets to compare the lncRNA expression profiles of tumor and paired normal tissues. hybridization of tissue sections was performed to validate the expression data and determine the localization of lncRNAs that may be linked to glioblastoma and colon adenocarcinoma. Chromatin isolation by RNA purification (ChIRP), chromatin immunoprecipitation (ChIP), and Co-immunoprecipitation (Co-IP) assays were performed to assess the interaction between lncRNA, proteins, and chromatin. The functional significance of the identified lncRNAs was verified and by knockdown or exogenous expression experiments. We found a lncRNA ENST00000449248.1 termed PRC2 and DDX5 associated lncRNA (PRADX) that is highly expressed in glioblastoma and colon adenocarcinoma cells and tissues. PRADX, mainly located in the nucleus of tumor cells, could bind to EZH2 protein via the 5' terminal sequence. Moreover, PRADX increased the trimethylation of H3K27 in the UBXN1 gene promoter via PRC2/DDX5 complex recruitment and promoted NF-κB activity through UBXN1 suppression. Knockdown of PRADX significantly inhibited tumor cell viability and clonogenic growth . In xenograft models, PRADX knockdown suppressed tumor growth and tumorigenesis and prolonged the survival of tumor-bearing mice. PRADX acts as a cancer driver and may serve as a potential therapeutic target for glioblastoma and colon adenocarcinoma.
越来越多的证据表明，长非编码 RNA（lncRNA）在癌症进展中发挥着关键作用；然而，仅有少数 lncRNA 被详细描述。本研究旨在鉴定胶质母细胞瘤和结肠腺癌中的新型癌症驱动 lncRNA。我们对 TCGA 泛癌症数据集进行了全转录组分析，以比较肿瘤和配对正常组织的 lncRNA 表达谱。通过组织切片杂交验证表达数据，并确定可能与胶质母细胞瘤和结肠腺癌相关的 lncRNA 的定位。通过 RNA 纯化染色质免疫沉淀（ChIRP）、染色质免疫沉淀（ChIP）和共免疫沉淀（Co-IP）实验评估 lncRNA、蛋白质和染色质之间的相互作用。通过敲低或外源性表达实验验证鉴定的 lncRNA 的功能意义。我们发现了一种在胶质母细胞瘤和结肠腺癌细胞和组织中高表达的 lncRNA，命名为 PRC2 和 DDX5 相关 lncRNA（PRADX）。PRADX 主要位于肿瘤细胞的核内，可通过 5'端序列与 EZH2 蛋白结合。此外，PRADX 通过 PRC2/DDX5 复合物募集增加 UBXN1 基因启动子上 H3K27 的三甲基化，并通过抑制 UBXN1 促进 NF-κB 活性。敲低 PRADX 显著抑制肿瘤细胞活力和克隆形成。在异种移植模型中，敲低 PRADX 抑制肿瘤生长和肿瘤发生，并延长荷瘤小鼠的生存时间。PRADX 作为一种癌症驱动因子，可能成为胶质母细胞瘤和结肠腺癌的潜在治疗靶点。
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