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Nucleolin facilitates nuclear retention of an ultraconserved region containing TRA2?4 and accelerates colon cancer cell growth.

ABSTRACT: Transcribed-ultraconserved regions (T-UCRs), which contain conserved sequences with 100% identity across human, rat and mouse species, are a novel category of functional RNAs. The human transformer 2? gene (TRA2B) encodes a UCR that spans exon 2 (276 bp) and its neighboring introns. Among five spliced RNA variants (TRA2?1-5) transcribed from the TRA2B gene, only TRA2?4 contains the conserved exon 2. TRA2?4 is overexpressed in colon cancer cells and accelerates cell growth by blocking the transcription of CDKN1A. However, the mechanisms underlying the overexpression of TRA2?4 in colon cancer cells are unknown. Using biotinylated RNA pull-down assays followed by liquid chromatography-mass spectrometric analysis, we identified nucleolin as a TRA2?4-binding protein. Knockdown of nucleolin reduced the nuclear retention of TRA2?4 and accelerated its degradation in the cytoplasm, whereas nucleolin overexpression increased TRA2?4 levels and its mitogenic activity. Nucleolin directly bound to TRA2?4 exon 2 via the glycine/arginine-rich (GAR) domain. Overexpression of GAR-deficient nucleolin failed to increase TRA2?4 expression and growth of colon cancer cells. RNA fluorescence in situ hybridization showed that TRA2?4 co-localized with nucleolin in nuclei but not with the mutant lacking GAR. Our results suggest that specific interactions between nucleolin and UCR-containing TRA2?4 may be associated with abnormal growth of colon cancer cells.

SUBMITTER: Satake Y

PROVIDER: S-EPMC6003563 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Nucleolin facilitates nuclear retention of an ultraconserved region containing TRA2β4 and accelerates colon cancer cell growth.

Satake Yuzuru Y Kuwano Yuki Y Nishikawa Tatsuya T Fujita Kinuyo K Saijo Saki S Itai Miki M Tanaka Hiroki H Nishida Kensei K Rokutan Kazuhito K

Oncotarget 20180601 42

Transcribed-ultraconserved regions (T-UCRs), which contain conserved sequences with 100% identity across human, rat and mouse species, are a novel category of functional RNAs. The human transformer 2β gene (TRA2B) encodes a UCR that spans exon 2 (276 bp) and its neighboring introns. Among five spliced RNA variants (TRA2β1-5) transcribed from the TRA2B gene, only TRA2β4 contains the conserved exon 2. TRA2β4 is overexpressed in colon cancer cells and accel ...[more]

PMID: 29928487

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Project description:Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for early diagnosis and prognosis as well as for development of new RNA-based cancer therapies.

Dataset Information

Nucleolin facilitates nuclear retention of an ultraconserved region containing TRA2?4 and accelerates colon cancer cell growth.

Publications

Nucleolin facilitates nuclear retention of an ultraconserved region containing <i>TRA2β4</i> and accelerates colon cancer cell growth.

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