Triplex-forming oligonucleotides as an anti-gene technique for cancer therapy

Li, Chun; Zhou, Zunzhen; Ren, Chao; Deng, Yi Zhen; Peng, Feng; Wang, Qiongfen; Zhang, Hong; Jiang, Yimei

doi:10.3389/fphar.2022.1007723

Cited by 15 publications

(9 citation statements)

References 72 publications

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“…Since LINC01137 was the molecule that facilitated the unraveling of relationships, we employed other modules of the ncFANs tool to further investigate if any other dependencies with the rest of the core network exist. 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.…”

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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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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“…With known site-specific effects, triplex formation presents a fascinating approach for specific targeting of DNA sequences, specifically as an anti-gene technique in cancer (2,10,11). The most common use of TFO technology includes gene modulation and gene modification at DNA level (10).…”

Section: Introductionmentioning

confidence: 99%

“…Triplex formation is a promising cancer treatment as an anti-gene technique, capable of specific DNA sequence targeting (2,8,9). TFOs can direct sequence-specific DNA damage whether they are bound to another compound or by themself (2,10), and they can facilitate site-specific DNA repair synthesis and mutagenesis, likely via the nucleotide excision repair (NER) mechanism (2,11).…”

Section: Introductionmentioning

confidence: 99%

TTSBBC: Triplex Target Site Biomarkers and Barcodes in Cancer

Ylagan,

Xu,

Kowalski

2024

Preprint

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The technology of Triplex-forming oligonucleotides (TFOs) provides an approach to manipulate genes at the DNA level. TFOs bind to specific sites on double-stranded DNA, creating a unique triple-helix DNA structure through Hoogsteen hydrogen bonding. This targeting by TFOs is site-specific and the locations TFOs bind are commonly referred to as TFO target sites (TTS). Triplexes have been observed to influence gene expression selectively, stimulate homologous recombination, trigger mutations, inhibit protein binding, and direct DNA damage. These sites typically feature a poly-purine sequence in duplex DNA, and the characteristics of these TTS sequences greatly influence the formation of the triplex. We introduce TTSBBC, a novel analysis and visualization platform designed to explore these features of TTS sequences. The web server can be freely accessed at https://kowalski-labapps.dellmed.utexas.edu/TTSBBC/ .

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“…This triplex formation can suppress gene expression by inhibiting transcription factor binding or preventing RNA polymerase elongation [2] . Researchers have focused on suppressing clinically important oncogenes, such as c‐myc , bcl‐2 , HER2/neu , and Ets‐2 genes [2c] . Some studies have incorporated crosslinkable molecules into TFOs, requiring covalent bond formation to suppress target gene expression [3] .…”

Section: Introductionmentioning

confidence: 99%

Development and Crosslinking Properties of Psoralen‐Conjugated Triplex‐Forming Oligonucleotides as Antigene Tools Targeting Genome DNA

Mikame,

Eshima,

Toyama

et al. 2023

ChemMedChem

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Psoralen‐conjugated triplex‐forming oligonucleotides (Ps‐TFOs) have been utilized for genome editing and anti‐gene experiments for over thirty years. However, the research on Ps‐TFOs employing artificial nucleotides is still limited, and their photo‐crosslinking properties have not been thoroughly investigated in relation to biological activities. In this study, we extensively examined the photo‐crosslinking properties of Ps‐TFOs to provide fundamental insights for future Ps‐TFO design. We developed novel Ps‐TFOs containing 2'‐O,4'‐C‐methylene‐bridged nucleic acids (Ps‐LNA‐mixmer) and investigated their photo‐crosslinking properties using stable cell lines that express firefly luciferase constitutively to evaluate the anti‐gene activities of Ps‐LNA‐mixmer. As a result, Ps‐LNA‐mixmer successfully demonstrated suppression activity, and we presented the first‐ever correlation between photo‐crosslinking properties and their activities. However, our findings indicate that the photo‐crosslinking process is insufficient under cell irradiation conditions (365 nm, 2 mW/cm2, 60 min). Therefore, our results highlight the need to develop new psoralen derivatives that are more reactive under cell irradiation conditions.

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Triplex-forming oligonucleotides as an anti-gene technique for cancer therapy

Cited by 15 publications

References 72 publications

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

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

TTSBBC: Triplex Target Site Biomarkers and Barcodes in Cancer

Development and Crosslinking Properties of Psoralen‐Conjugated Triplex‐Forming Oligonucleotides as Antigene Tools Targeting Genome DNA

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