LncRNA PRADX-mediated recruitment of PRC2/DDX5 complex suppresses UBXN1 expression and activates NF-κB activity, promoting tumorigenesis

Abstract

Rationale: 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. Methods: We performed whole transcriptome analysis of TCGA pan-cancer datasets to compare the lncRNA expression profiles of tumor and paired normal tissues. In situ 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 in vitro and in vivo by knockdown or exogenous expression experiments. Results: 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 vitro . In xenograft models, PRADX knockdown suppressed tumor growth and tumorigenesis and prolonged the survival of tumor-bearing mice. Conclusions: PRADX acts as a cancer driver and may serve as a potential therapeutic target for glioblastoma and colon adenocarcinoma.

YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m6A modification to activate NF-κB and promote the malignant progression of glioma

“…S6). Next, we focused on the relationship between YTHDF2 and UBXN1, which could negatively regulate activation of NF-κB via different ways [ 20 , 31 ].…”

“…Recently, downregulation of UBXN1 expression was also reported to be involved in the mechanism by which EGFR promotes NF-κB activation and the mechanism through which the long non-coding RNA, PRADX, activates NF-κB [ 20 , 21 ]. Meanwhile, EGFR-YTHDF2 coupling can stabilize the YTHDF2 protein, which can promote GBM tumorigenesis by enhancing degradation of LXRA and HIVEP2 mRNA [ 19 ].…”

“…These findings indicate that YTHDF2 may be involved in tumorigenesis and malignant progression of glioma through multiple pathways. Emerging evidence shows that activation of the NF-kB signaling pathway plays a core role in promoting the malignant progression of glioma [ 3 , 20 , 21 ]. However, whether YTHDF2 can modulate NF-kB activation in gliomas through m 6 A modification remains unclear.…”

The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma

“…It can also be subdivided into long no coding RNA (lncRNA), circular RNA (circRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), microRNA (miRNA), small interfering RNA (siRNA), and small nucleolar RNA (snoRNA) [ 24 – 27 ], etc. Among them, lncRNA and miRNA mainly mediate post-transcriptional regulation, the dysregulation of which was found associated with many malignant tumors [ 28 ].…”

Long Non-Coding RNA: A Potential Strategy for the Diagnosis and Treatment of Colorectal Cancer

“…Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that catalyzes histone H3 lysine 27 trimethylation (H3K27me3) and epigenetically silences target genes ( 10 ), is overexpressed in many cancer types and has been shown to act as an oncogene ( 11 , 12 ). PRADX can bind to the EZH2 protein through its 1-500 bp 5’ end sequence to recruit PRC2 and DDX5, forming a PRC2/DDX5 complex ( 13 ). Activation of the nuclear factor kappa B (NF-κB) pathway promotes the occurrence of colorectal adenocarcinoma.…”