DGCR8/ZFAT-AS1 Promotes CDX2 Transcription in a PRC2 Complex-Dependent Manner to Facilitate the Malignant Biological Behavior of Glioma Cells

• Published in: Molecular therapy 2020-02, Vol.28 (2), p.613-630
• Main Authors: Zhang, Fangfang, Ruan, Xuelei, Ma, Jun, Liu, Xiaobai, Zheng, Jian, Liu, Yunhui, Liu, Libo, Shen, Shuyuan, Shao, Lianqi, Wang, Di, Yang, Chunqing, Cai, Heng, Li, Zhen, Feng, Ziyi, Xue, Yixue
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - genetics; CDX2; CDX2 Transcription Factor - genetics; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; DGCR8; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; glioma; Glioma - genetics; Glioma - metabolism; Glioma - mortality; Glioma - pathology; H3K27me3; Humans; Mice; Original; Promoter Regions, Genetic; Protein Binding; RNA, Antisense; RNA, Long Noncoding - genetics; RNA-Binding Proteins - genetics; Transcription Factors - genetics; Xenograft Model Antitumor Assays; ZFAT-AS1
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.11.015

Studies have found that RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) are dysregulated and play an important regulatory role in the development of tumors. Based on The Cancer Genome Atlas (TCGA) database, our findings from experiments, and the evidence of previous studies, we screened DiGeorge syndrome critical region gene 8 (DGCR8), ZFAT antisense RNA 1 (ZFAT-AS1), and caudal type homeobox 2 (CDX2) as research candidates. In the present study, DGCR8 and CDX2 were highly expressed and ZFAT-AS1 was markedly downregulated in glioma tissues and cells. DGCR8 or CDX2 knockdown or ZFAT-AS1 overexpression suppressed glioma cell proliferation, migration, and invasion and facilitated apoptosis. DGCR8 might decrease ZFAT-AS1 expression by attenuating its stability in a manner of inducing its cleavage. Importantly, ZFAT-AS1 could inhibit CDX2 transcription by mediating the methylation of histone H3 on lysine 27 (H3K27me3) modification induced by PRC2 in the CDX2 promoter region. In addition, CDX2 transcriptionally activated DGCR8 expression by binding to its promoter regions, forming a positive feedback loop of DGCR8/ZFAT-AS1/CDX2. In conclusion, DGCR8/ZFAT-AS1 promotes CDX2 transcription in a PRC2 complex-dependent manner to facilitate the malignant biological behavior of glioma cells. [Display omitted] Yixue Xue et al. demonstrate that DGCR8 can decrease ZFAT-AS1 expression by attenuating its stability in a manner of inducing its cleavage. Importantly, ZFAT-AS1 can inhibit CDX2 transcription by mediating the H3K27me3 modification induced by PRC2 in the CDX2 promoter region, which can affect the malignant biological behavior of glioma cells.