Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
Cancer Research UK Lung Cancer Centre of Excellence, at Manchester and University College London, London, UK.
Cell Death Differ. 2021 Sep;28(9):2673-2689. doi: 10.1038/s41418-021-00777-0. Epub 2021 May 26.
AMP-activated protein kinase (AMPK) is a critical sensor of energy status that coordinates cell growth with energy balance. In non-small cell lung cancer (NSCLC) the role of AMPKα is controversial and its contribution to lung carcinogenesis is not well-defined. Furthermore, it remains largely unknown whether long non-coding RNAs (lncRNAs) are involved in the regulation of AMPK-mediated pathways. Here, we found that loss of AMPKα in combination with activation of mutant KRAS increased lung tumour burden and reduced survival in Kras/AMPKα mice. In agreement, functional in vitro studies revealed that AMPKα silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPKα-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPKα activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPKα loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPKα axis that could be exploited for therapeutic purposes.
AMP 激活的蛋白激酶 (AMPK) 是能量状态的关键传感器，它协调细胞生长与能量平衡。在非小细胞肺癌 (NSCLC) 中，AMPKα 的作用存在争议，其对肺癌发生的贡献尚不清楚。此外，长链非编码 RNA (lncRNA) 是否参与调节 AMPK 介导的通路在很大程度上仍然未知。在这里，我们发现 AMPKα 的缺失与突变 KRAS 的激活相结合，增加了 Kras/AMPKα 小鼠的肺肿瘤负担并降低了其存活率。一致地，功能体外研究表明 AMPKα 的沉默增加了 NSCLC 细胞的生长和迁移。此外，我们鉴定了一个 AMPKα 调节的 lncRNA，KIMAT1（ENSG00000228709），它通过稳定乳酸脱氢酶 B (LDHB) 来调节 AMPKα 的激活。总之，我们的研究表明 AMPKα 的缺失促进了 KRAS 介导的肺肿瘤发生，并提出了一个新的 KRAS/KIMAT1/LDHB/AMPKα 轴，可用于治疗目的。
