Long noncoding RNA (lncRNA) capable of controlling antioxidative capacity remains to be investigated. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a central molecule for cellular defense that increases antioxidative capacity. We identified a novel lncRNA named Nrf2-activating lncRNA (Nrf2-lncRNA) transcribed from an upstream region of the microRNA 122 gene (MIR122). Nrf2-lncRNA existed in the cytoplasm, suggestive of its function as a competing endogenous RNA ceRNA, microRNA (miRNA) sponge. Nrf2-lncRNA served as a ceRNA for polo-like kinase (Plk) 2 and cyclin-dependent kinase inhibitor 1 (p21(cip1)) through binding of miRNA 128 and miRNA 224, inducing Plk2/Nrf2/p21(cip1) complexation for Nrf2 activation in the cells under p53-activating conditions (i.e., DNA damage and serum deprivation). Nrf2-lncRNA expression was suppressed with the initiation of apoptosis, being a rheostat for cell fate determination. Nrf2-lncRNA levels correlated with the recurrence-free postsurgery survival rate of patients with hepatocellular carcinoma. Collectively, Nrf2-lncRNA promotes Plk2 and p21(cip1) translation by competing for specific miRNAs and activating Nrf2 under surviving conditions from oxidative stress, implying that Nrf2-lncRNA serves as a fine-tuning rheostat for cell fate decision.-Joo, M. S., Shin, S.-B., Kim, E. J., Koo, J. H., Yim, H., Kim, S. G. Nrf2-lncRNA controls cell fate by modulating p53-dependent Nrf2 activation as an miRNA sponge for Plk2 and p21(cip1).
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