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.
| Original language | English |
|---|---|
| Pages (from-to) | 4910-4925 |
| Number of pages | 16 |
| Journal | Cancer Research |
| Volume | 81 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - 1 Oct 2021 |
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Long noncoding RNA NIHCOLE promotes ligation efficiency of DNA double-strand breaks in hepatocellular carcinoma. / Unfried, Juan P.; Marín-Baquero, Mikel; Rivera-Calzada, Ángel et al.
In: Cancer Research, Vol. 81, No. 19, 01.10.2021, p. 4910-4925.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Long noncoding RNA NIHCOLE promotes ligation efficiency of DNA double-strand breaks in hepatocellular carcinoma
AU - Unfried, Juan P.
AU - Marín-Baquero, Mikel
AU - Rivera-Calzada, Ángel
AU - Razquin, Nerea
AU - Martín-Cuevas, Eva M.
AU - de Bragança, Sara
AU - Aicart-Ramos, Clara
AU - McCoy, Christopher
AU - Prats-Mari, Laura
AU - Arribas-Bosacoma, Raquel
AU - Lee, Linda
AU - Caruso, Stefano
AU - Zucman-Rossi, Jessica
AU - Sangro, Bruno
AU - Williams, Gareth
AU - Moreno-Herrero, Fernando
AU - Llorca, Oscar
AU - Lees-Miller, Susan P.
AU - Fortes, Puri
N1 - Funding Information: J.P. Unfried reports grants from Ministry of Economy and Competitiveness, MCIU/AEI/FEDER, Gobierno de Navarra, Scientific Foundation of the Spanish Association Against Cancer, and University of Navarra’s Asociación de Amigos Foundation during the conduct of the study; in addition, J.P. Unfried has a patent for NIHCOLE in HCC pending. A. Rivera-Calzada reports grants from Autonomous Region of Madrid (Ref: S2018/NMT-4443) and Autonomous Region of Madrid (Ref: Y2018/BIO-4747) during the conduct of the study. N. Razquin reports grants from Ministry of Economy and Competitiveness, MCIU/AEI/FEDER, Gobierno de Navarra, and Scientific Foundation of the Spanish Association Against Cancer during the conduct of the study. C. McCoy reports grants from NSERC, CFI, and NIH during the conduct of the study. L. Prats-Mari reports Ministry of Economy and Competitiveness, MCIU/AEI/FEDER, Gobierno de Navarra, Scientific Foundation of the Spanish Association Against Cancer, and National Institute of Health Carlos III during the conduct of the study. S. Caruso reports grants from CARPEM and Labex outside the submitted work. B. Sangro reports grants from National Institute of Health Carlos III. Fondo de Investigación Sanitaria (PI19/00742 to B. Sangro) during the conduct of the study; personal fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, BTG, Eisai, Eli Lilly, H3 Biomedicine, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo, and grants from Bristol Myers Squibb and Sirtex Medical outside the submitted work. G. Williams reports grants from NSERC, CFI, and NIH during the conduct of the study. F. Moreno-Herrero reports grants from Autonomous Region of Madrid (Ref: S2018/NMT-4443), Autonomous Region of Madrid (Ref: Y2018/BIO-4747), European Research Council (grant agreement 681299), and Ministry of Economy and Competitiveness [Ref: BFU2017–83794-P (AEI/FEDER, UE)] during the conduct of the study. O. Llorca reports grants from Autonomous Region of Madrid (Ref: S2018/NMT-4443)) and grants from Autonomous Region of Madrid (Ref: Y2018/BIO-4747) during the conduct of the study. S.P. Lees-Miller reports grants from NIH/NCI during the conduct of the study. P. Fortes reports grants from Ministry of Economy and Competitiveness, MCIU/AEI/FEDER, Gobierno de Navarra, and Scientific Foundation of the Spanish Association Against Cancer during the conduct of the study; grants from Foundation LaCaixa and Columbia-Tyris outside the submitted work; in addition, P. Fortes has a patent for NIHCOLE in HCC pending. No disclosures were reported by the other authors. Funding Information: The authors particularly acknowledge the patients for their participation and the Biobank of the University of Navarra for its collaboration. They thank all members of the Fortes Lab for helpful discussions and Guillermo Serrano and Dr. Victor Segura from CIMA bioinformatics unit for excellent expert assistance. They thank R. Ye and Dr. Anne Vaahtokari for technical assistance, S. Fang (University of Calgary) for purification of XRCC4 and APLF, and Dr. Laurence H. Pearl (Genome Damage and Stability Centre, School of Life Sciences, University of Sussex) for providing X4L4 and Ku70/80 for some of the experiments in this work. The authors also thank the flow cytometry facility and the Arnie Charbonneau microscopy facility at Cumming School of Medicine, University of Calgary for expert assistance. The results shown here are in part based upon data generated by the TCGA Research Network (http:// cancergenome.nih.gov/) and by the GTEx Project (https://gtexportal.org/). Figures 3A and E and 7; Supplementary Fig. S3H were created with BioRender.com. This work was supported by the European FEDER funding (to the activities of the groups directed by P. Fortes, O. Llorca, and F. Moreno-Herrero) and grants from the Ministry of Economy and Competitiveness [SAF2015-70971-R to P. Fortes and BFU2017-83794-P (AEI/FEDER, UE) to F. Moreno-Herrero)]; MCIU/AEI/FEDER/UE (RTI2018-101759-B-I00 to P. Fortes), NIH program (CA92584 to S.P. Lees-Miller), Ligue National Contre le Cancer, Équipe Labellisée and ITMO Cancer: Consortium HETCOLI (to J. Zucman-Rossi), NIH program (P01CA092584 to G. Williams), NSERC (RGPIN-2018-04327 to G. Williams), and CFI (RCP-18-023-SEG to G. Williams), Gobierno de Navarra (33/2015 to P. Fortes), Scientific Foundation of the Spanish Association Against Cancer (AECC IDEAS20169FORT to P. Fortes); Fondo de Investigación Sanitaria (PI19/00742 to B. Sangro), financed by the National Institute of Health Carlos III and FEDER. CNIO and CIBERehd are funded by the National Institute of Health Carlos III. J.P. Unfried was a recipient of a University of Navarra’s Asociación de Amigos fellowship. L. Prats-Mari is a recipient of a PFIS fellowship (FI20/00074) by the National Institute of Health Carlos III and FSE "Investing in Your Future." This work was also funded by grants from the Autonomous Region of Madrid (Tec4Bio—S2018/NMT-4443 and NanoBioCancer— Y2018/BIO-4747 to O. Llorca and F. Moreno-Herrero) and co-funded by the European Social Fund. F. Moreno-Herrero acknowledges support from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 681299). The GTEx Project was supported by the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Funding Information: The authors particularly acknowledge the patients for their participation and the Biobank of the University of Navarra for its collaboration. They thank all members of the Fortes Lab for helpful discussions and Guillermo Serrano and Dr. Victor Segura from CIMA bioinformatics unit for excellent expert assistance. They thank R. Ye and Dr. Anne Vaahtokari for technical assistance, S. Fang (University of Calgary) for purification of XRCC4 and APLF, and Dr. Laurence H. Pearl (Genome Damage and Stability Centre, School of Life Sciences, University of Sussex) for providing X4L4 and Ku70/80 for some of the experiments in this work. The authors also thank the flow cytometry facility and the Arnie Charbonneau microscopy facility at Cumming School of Medicine, University of Calgary for expert assistance. The results shown here are in part based upon data generated by the TCGA Research Network (http://cancergenome.nih.gov/) and by the GTEx Project (https://gtexportal.org/). Figures 3A and E and 7; Supplementary Fig. S3H were created with BioRender.com. This work was supported by the European FEDER funding (to the activities of the groups directed by P. Fortes, O. Llorca, and F. Moreno-Herrero) and grants from the Ministry of Economy and Competitiveness [SAF2015-70971-R to P. Fortes and BFU2017-83794-P (AEI/FEDER, UE) to F. Moreno-Herrero)]; MCIU/AEI/FEDER/UE (RTI2018-101759-B-I00 to P. Fortes), NIH program (CA92584 to S.P. Lees-Miller), Ligue National Contre le Cancer, ?quipe Labellis?e and ITMO Cancer: Consortium HETCOLI (to J. Zucman-Rossi), NIH program (P01CA092584 to G. Williams), NSERC (RGPIN-2018-04327 to G. Williams), and CFI (RCP-18-023-SEG to G. Williams), Gobierno de Navarra (33/2015 to P. Fortes), Scientific Foundation of the Spanish Association Against Cancer (AECC IDEAS20169FORT to P. Fortes); Fondo de Investigacion Sanitaria (PI19/00742 to B. Sangro), financed by the National Institute of Health Carlos III and FEDER. CNIO and CIBERehd are funded by the National Institute of Health Carlos III. J.P. Unfried was a recipient of a University of Navarra?s Asociacion de Amigos fellowship. L. Prats-Mari is a recipient of a PFIS fellowship (FI20/00074) by the National Institute of Health Carlos III and FSE "Investing in Your Future." This work was also funded by grants from the Autonomous Region of Madrid (Tec4Bio?S2018/NMT-4443 and NanoBioCancer?Y2018/BIO-4747 to O. Llorca and F. Moreno-Herrero) and co-funded by the European Social Fund. F. Moreno-Herrero acknowledges support from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 681299). The GTEx Project was supported by the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Publisher Copyright: © 2021 American Association for Cancer Research
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
U2 - 10.1158/0008-5472.CAN-21-0463
DO - 10.1158/0008-5472.CAN-21-0463
M3 - Article
C2 - 34321241
AN - SCOPUS:85116009077
VL - 81
SP - 4910
EP - 4925
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 19
ER -