학술논문
Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma.
Document Type
Academic Journal
Author
Unfried JP; Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain. junfried@unav.es pfortes@unav.es.; Marín-Baquero M; Department of Macromolecular Structures, Spanish National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain.; Rivera-Calzada Á; Structural Biology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.; Razquin N; Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain.; Martín-Cuevas EM; Department of Macromolecular Structures, Spanish National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain.; de Bragança S; Department of Macromolecular Structures, Spanish National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain.; Aicart-Ramos C; Department of Macromolecular Structures, Spanish National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain.; McCoy C; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Prats-Mari L; Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain.; Arribas-Bosacoma R; Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK.; Lee L; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Caruso S; Centre 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.; Zucman-Rossi J; Centre 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.; Sangro B; University of Navarra Clinic (CUN), Liver Unit, Pamplona, Spain.; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.; Liver and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain.; Williams G; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Moreno-Herrero F; Department of Macromolecular Structures, Spanish National Centre for Biotechnology (CNB), Spanish National Research Council (CSIC), Madrid, Spain.; Llorca O; Structural Biology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.; Lees-Miller SP; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Fortes P; Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research (CIMA), University of Navarra (UNAV), Pamplona, Spain. junfried@unav.es pfortes@unav.es.; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.; Liver and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain.
Source
Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
Subject
Language
English
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 .
(©2021 American Association for Cancer Research.)
(©2021 American Association for Cancer Research.)