Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma
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Abstract
Long noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of blunt-ended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability. Significance: This study characterizes the role of lncRNA NIHCOLE in DNA repair and cellular fitness in HCC, thus implicating it as a therapeutic target. See related commentary by Barcena-Varela and Lujambio, p. 4899
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The genes with promoter DNA hypomethylation include AFP, several HCC-related lncRNAs (LINC01419, LINC02163, LINC02835), and tumor-associated antigens such as the MAGE gene family.
“These genes included AFP, a diagnostic marker for HCC, several HCC-related lncRNAs (LINC01419, LINC02163, and LINC02835), and tumor-associated antigens such as the MAGE gene family35–37.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [35]
The Results section identifies LINC02163 as NIHCOLE, an lncRNA highly expressed in HCC. It does not report promoter DNA hypomethylation for LINC02163 or the listed genes, and the passages do not establish the other named genes as members of the claimed group. No page number is available in our copy. (LLM, conf=0.82)
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Cited by
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Cheng, C. C. Y., Cheung, M. F., Lee, A. Y., Wu, Q., Chow, S. H.-C., Ang, J. Y. J., Riquelme Medina, I., Lo, G., Wu, H., Yang, W., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-09154-w · Cited by 3 · see citing works
- Authors
- Unfried, J. P., Marín-Baquero, M., Rivera-Calzada, Á., Razquin, N., Martín-Cuevas, E. M., de Bragança, S., Aicart-Ramos, C., McCoy, C., Prats-Mari, L., Arribas-Bosacoma, R., Lee, L., Caruso, S., Zucman-Rossi, J., Sangro, B., Williams, G., Moreno-Herrero, F., Llorca, O., Lees-Miller, S. P., & Fortes, P.
- Affiliations
- Centro de Investigación Médica Aplicada (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Spanish National Cancer Research Centre (ES)
- 2Department of Macromolecular Structures, Spanish National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain.
- University of Calgary (CA)
- University of Sussex (GB)
- Inserm (FR)
- 6Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Functional Genomics of Solid Tumors laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France.
- Navarre Institute of Health Research (ES)
- 3Structural Biology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
- 4Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
- Corresponding author
- Unfried, Juan P.
- Fortes, Puri
- ORCID
- Venue
- Cancer Research
- Published
- 2021-07-28
- Volume
- 81
- Issue
- 19
- Pages
- 4910-4925
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC8488005
- OpenAlex
- W3183730523
- Cited by
- 48
- References
- 0
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 13 · 2023: 12 · 2022: 11 · 2021: 5
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Ministry of Economy and Competitiveness (SAF2015-70971-R, BFU2017-83794-P)
- MCIU/AEI/FEDER/UE (RTI2018-101759-B-I00)
- NIH (P01CA092584)
- NSERC (RGPIN-2018-04327)
- CFI (RCP-18-023-SEG)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Keywords
- long non-coding RNA, hepatocellular carcinoma, DNA double-strand break repair, non-homologous end joining, Ku70/Ku80, DNA ligase IV, DNA damage response, cell proliferation, apoptosis, prognostic factors, therapeutic target
- MeSH terms
- Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Models, Biological, Nucleic Acid Conformation, Prognosis, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Gene Expression Profiling, Cell Line, Tumor, DNA Breaks, Double-Stranded, High-Throughput Nucleotide Sequencing, Nucleotide Motifs, DNA End-Joining Repair, RNA, Long Noncoding
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