Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma.

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 lig...

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Bibliographic Details
Authors: Unfried, Juan P, Marín-Baquero, Mikel, Rivera-Calzada, Ángel, Razquin, Nerea, Martín-Cuevas, Eva M, de Bragança, Sara, Aicart-Ramos, Clara, McCoy, Christopher, Prats-Mari, Laura, Arribas-Bosacoma, Raquel, Lee, Linda, Caruso, Stefano, Zucman-Rossi, Jessica, Sangro, Bruno, Williams, Gareth, Moreno-Herrero, Fernando, Llorca Blanco, Oscar Antonio, Lees-Miller, Susan P, Fortes, Puri, Llorca, Oscar, Unfried, Juan P., Martín-Cuevas, Eva M.
Format: article
Publication Date:2021
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/23088
Online Access:https://hdl.handle.net/20.500.12105/23088
Access Level:Open access
Keyword:DNA Breaks, Double-Stranded
Biomarkers, Tumor
Carcinoma, Hepatocellular
Cell Line, Tumor
DNA End-Joining Repair
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
High-Throughput Nucleotide Sequencing
Humans
Liver Neoplasms
Models, Biological
Nucleic Acid Conformation
Nucleotide Motifs
Prognosis
RNA, Long Noncoding
Description
Summary: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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