Abstract
Long noncoding RNAs (lncRNAs) are involved in a variety of cancers, but the role of LncRNA DUBR in lung adenocarcinoma (LUAD), the most prevalent form of lung cancer, remains unclear. In this study we investigated the expression of DUBR in LUAD to ascertain its association with the clinical pathology and prognosis of LUAD. Analysis of mRNA expression in The Cancer Genome Atlas (TCGA) LUAD database and in-house LUAD cohort (n = 94) showed that DUBR was significantly downregulated in LUAD, and was associated with poor prognosis. In LUAD cell lines (H1975, A549), overexpression of DUBR significantly suppressed the migration and invasion of the LUAD cells. We demonstrated that c-Myc could bind to the promoter of DUBR, and transcriptionally suppressed its expression. Knockdown of c-Myc almost completely blocked the invasion and migration of LUAD cells, whereas knockdown of DUBR partially rescued c-Myc-knockdown suppressed cell migration and invasion. Furthermore, DUBR overexpression significantly increased the expression of a downstream protein of DUBR, zinc finger, and BTB domain containing 11 (ZBTB11), in H1975 and A549 cells; knockdown of ZBTB11 partially rescued the DUBR-overexpression suppressed cell migration and invasion; knockdown of c-Myc significantly upregulated the expression of ZBTB11 in LUAD cells. Finally, we revealed that DUBR/ZBTB11 axis suppressed oxidative phosphorylation in LUAD cells. In short, we demonstrate that c-Myc/DUBR/ZBTB11 axis suppresses migration and invasion of LUAD by attenuating cell oxidative phosphorylation, which provides new insights into the regulatory mechanism of DUBR.
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Acknowledgements
This research was financially supported by National Natural Science Foundation of China (No. 81601988), the Shanghai Science and Technology Development fund (No. 19MC1911000), Hospital Foundation of Fudan University Shanghai Cancer Center (No. YJMS201907), and Shanghai Chest Hospital Project of Collaborative Innovation (No. YJXT20190102).
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BHH, MDX, and WN participated in the design of the study. JL, LLZ, SHC, and JWL carried out experiments and collected the data. MJH, FH, and CHL analyzed experimental data and conducted graphs and tables. FFQ, YW, QZ, and XYZ performed bioinformatics analysis. MJH and QZ wrote the paper. BHH, MDX, and WN reviewed the paper. All authors read and approved the final paper.
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Nie, W., Hu, Mj., Zhang, Q. et al. DUBR suppresses migration and invasion of human lung adenocarcinoma cells via ZBTB11-mediated inhibition of oxidative phosphorylation. Acta Pharmacol Sin 43, 157–166 (2022). https://doi.org/10.1038/s41401-021-00624-5
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DOI: https://doi.org/10.1038/s41401-021-00624-5
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