Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
Acta Pharmacol Sin. 2022 Jan;43(1):157-166. doi: 10.1038/s41401-021-00624-5. Epub 2021 Mar 23.
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.
长链非编码 RNA（lncRNA）参与多种癌症，但 lncRNA DUBR 在肺腺癌（LUAD）中的作用仍不清楚，LUAD 是最常见的肺癌形式。在这项研究中，我们研究了 DUBR 在 LUAD 中的表达，以确定其与 LUAD 的临床病理和预后的关系。对癌症基因组图谱（TCGA）LUAD 数据库和内部 LUAD 队列（n=94）的 mRNA 表达分析表明，DUBR 在 LUAD 中显著下调，并与预后不良相关。在 LUAD 细胞系（H1975、A549）中，DUBR 的过表达显著抑制了 LUAD 细胞的迁移和侵袭。我们证明 c-Myc 可以结合 DUBR 启动子，并转录抑制其表达。c-Myc 的敲低几乎完全阻断了 LUAD 细胞的侵袭和迁移，而 DUBR 的敲低部分挽救了 c-Myc 敲低抑制的细胞迁移和侵袭。此外，DUBR 的过表达显著增加了 DUBR 下游蛋白锌指和 BTB 结构域包含蛋白 11（ZBTB11）在 H1975 和 A549 细胞中的表达；ZBTB11 的敲低部分挽救了 DUBR 过表达抑制的细胞迁移和侵袭；c-Myc 的敲低显著上调了 LUAD 细胞中 ZBTB11 的表达。最后，我们揭示了 DUBR/ZBTB11 轴通过抑制 LUAD 细胞的氧化磷酸化来抑制细胞迁移和侵袭。总之，我们证明 c-Myc/DUBR/ZBTB11 轴通过减弱细胞氧化磷酸化来抑制 LUAD 的迁移和侵袭，为 DUBR 的调控机制提供了新的见解。
