Role of Nuclear Non-Canonical Nucleic Acid Structures in Organismal Development and Adaptation to Stress Conditions

Alecki, Célia; Vera, María

doi:10.3389/fgene.2022.823241

Cited by 5 publications

(2 citation statements)

References 138 publications

(197 reference statements)

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“…It has been reported that DNA-RNA triplex, a non-canonical nucleic acid structures, participates in the transcriptional activation through recruiting transcription factors, 27 among which hnRNPA2B1 has been previously reported to involve in H3K4 trimethylation (H3K4me3) at target genes to further activate their transcription. 13 , 28 Therefore, we sought to examine whether circTLCD4-RWDD3 activated UBC9 transcription by directly interacting with UBC9 promoter to recruit hnRNPA2B1 and induce the H3K4me3 on UBC9 promoter.…”

Section: Resultsmentioning

confidence: 99%

SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer

Diao,

Guo,

Zheng

et al. 2023

Sig Transduct Target Ther

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Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory prognosis of patients. Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis, the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear. In this study, we employed high-throughput sequencing to identify a novel circular RNA (circRNA), circTLCD4-RWDD3, which was significantly upregulated in extracellular vesicles (EVs) from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort. Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo. Mechanically, circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9. Subsequently, circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif (SIM) of ALIX and activated ALIX to recruit ESCRT-III, thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs. Moreover, EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1, resulting in the lymphangiogenesis and LN metastasis of NSCLC. Importantly, blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo. Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC, suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.

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Section: Resultsmentioning

confidence: 99%

SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer

Diao,

Guo,

Zheng

et al. 2023

Sig Transduct Target Ther

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“…Interestingly, not only was LINC01137 confirmed to co-express with ZC3H12A (r > 0.5; FDR <0.05; certifying their co-regulation under the divergent promoter), but it also forms the RNA–DNA triple helix (also known as triplex) in the genomic location of WWOX using 14 TFOs [typically, TFOs are 12–28 in length ( Li et al, 2022 )]. Such structures can repress or induce gene expression ( Alecki and Vera, 2022 ; Cecconello et al, 2022 ; Warwick et al, 2023 ), but the latter can be assumed in our case. The module evaluating triple helices also returned one TFO within the ZC3H12A gene, which should be noted for future studies.…”

Section: Resultsmentioning

confidence: 99%

LINC01137/miR-186-5p/WWOX: a novel axis identified from WWOX-related RNA interactome in bladder cancer

et al. 2023

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Introduction: The discovery of non-coding RNA (ncRNA) dates back to the pre-genomics era, but the progress in this field is still dynamic and leverages current post-genomics solutions. WWOX is a global gene expression modulator that is scarcely investigated for its role in regulating cancer-related ncRNAs. In bladder cancer (BLCA), the link between WWOX and ncRNA remains unexplored. The description of AP-2α and AP-2γ transcription factors, known as WWOX-interacting proteins, is more commonplace regarding ncRNA but still merits investigation. Therefore, this in vitro and in silico study aimed to construct an ncRNA-containing network with WWOX/AP-2 and to investigate the most relevant observation in the context of BLCA cell lines and patients.Methods: RT-112, HT-1376, and CAL-29 cell lines were subjected to two stable lentiviral transductions. High-throughput sequencing of cellular variants (deposited in the Gene Expression Omnibus database under the GSE193659 record) enabled the investigation of WWOX/AP-2-dependent differences using various bioinformatics tools (e.g., limma-voom, FactoMineR, multiple Support Vector Machine Recursive Feature Elimination (mSVM-RFE), miRDB, Arena-Idb, ncFANs, RNAhybrid, TargetScan, Protein Annotation Through Evolutionary Relationships (PANTHER), Gene Transcription Regulation Database (GTRD), or Evaluate Cutpoints) and repositories such as The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia. The most relevant observations from cap analysis gene expression sequencing (CAGE-seq) were confirmed using real-time PCR, whereas TCGA data were validated using the GSE31684 cohort.Results: The first stage of the whole study justified focusing solely on WWOX rather than on WWOX combined with AP-2α/γ. The most relevant observation of the developed ncRNA-containing network was LINC01137, i.e., long non-coding RNAs (lncRNAs) that unraveled the core network containing UPF1, ZC3H12A, LINC01137, WWOX, and miR-186-5p, the last three being a novel lncRNA/miRNA/mRNA axis. Patients’ data confirmed the LINC01137/miR-186-5p/WWOX relationship and provided a set of dependent genes (i.e., KRT18, HES1, VCP, FTH1, IFITM3, RAB34, and CLU). Together with the core network, the gene set was subjected to survival analysis for both TCGA-BLCA and GSE31684 patients, which indicated that the increased expression of WWOX or LINC01137 is favorable, similar to their combination with each other (WWOX↑ and LINC01137↑) or with MIR186 (WWOX↑/LINC01137↑ but MIR186↓).Conclusion: WWOX is implicated in the positive feedback loop with LINC01137 that sponges WWOX-targeting miR-186-5p. This novel WWOX-containing lncRNA/miRNA/mRNA axis should be further investigated to depict its relationships in a broader context, which could contribute to BLCA research and treatment.

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The Role of Methylation of a Group of microRNA Genes in the Pathogenesis of Metastatic Renal Cell Carcinoma

et al. 2023

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Role of Nuclear Non-Canonical Nucleic Acid Structures in Organismal Development and Adaptation to Stress Conditions

Cited by 5 publications

References 138 publications

SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer

SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer

LINC01137/miR-186-5p/WWOX: a novel axis identified from WWOX-related RNA interactome in bladder cancer

The Role of Methylation of a Group of microRNA Genes in the Pathogenesis of Metastatic Renal Cell Carcinoma

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