Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma.
Juan Pablo UnfriedMikel Marín-BaqueroAngel Rivera-CalzadaNerea RazquinEva M Martín-CuevasSara de BragançaClara Aicart-RamosChristopher McCoyLaura Prats-MariRaquel Arribas-BosacomaLinda LeeStefano CarusoJessica Zucman-RossiBruno SangroGareth WilliamsFernando Moreno-HerreroOscar LlorcaSusan P Lees-MillerPuri FortesPublished in: Cancer research (2021)
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.
Keyphrases
- dna repair
- dna damage
- poor prognosis
- cell cycle arrest
- long noncoding rna
- induced apoptosis
- long non coding rna
- oxidative stress
- endoplasmic reticulum stress
- cell free
- cell death
- end stage renal disease
- dna damage response
- single molecule
- newly diagnosed
- signaling pathway
- chronic kidney disease
- body composition
- climate change
- ejection fraction
- drug induced
- pi k akt
- binding protein
- physical activity
- peritoneal dialysis
- deep learning
- papillary thyroid
- high glucose
- artificial intelligence
- high throughput
- electronic health record
- network analysis