Lactate‐fueled oxidative metabolism drives DNA methyltransferase 1‐mediated transcriptional co‐activator with PDZ binding domain protein activation

• Published in: Cancer science 2020-01, Vol.111 (1), p.186-199
• Main Authors: Huang, Tao, Zhou, Xinglu, Mao, Xike, Yu, Chenxi, Zhang, Zhijian, Yang, Jianke, Zhang, Yao, Su, Tianyu, Chen, Chenchen, Cao, Yuxiang, Wei, Huijun, Wu, Zhihao
• Format: Article
• Language: English
• Subjects: AKT protein; Cell adhesion & migration; Cell Line, Tumor; Cloning; Dehydrogenases; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA methylation; DNA methyltransferase; DNA methyltransferase 1; DNMT1 protein; Gene expression; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - genetics; Glycolysis; Humans; Intracellular Signaling Peptides and Proteins - genetics; Invasiveness; Kinases; lactate; Lactic acid; Lactic Acid - metabolism; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mammals; Medical prognosis; Metabolism; Metastasis; Mitochondria; Original; Oxidative metabolism; Oxidative phosphorylation; Oxidative Stress - genetics; Phosphorylation; Promoter Regions, Genetic - genetics; Protein Binding - genetics; Proteins; Quantitative analysis; Reactive oxygen species; Reactive Oxygen Species - metabolism; TAZ; Trans-Activators - genetics; Transcription activation; Transcription, Genetic - genetics; Transcriptional Activation - genetics; Transducin; Ubiquitination
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14246

Activity of transcriptional co‐activator with PDZ binding domain (TAZ) protein is strongly implicated in the pathogenesis of human cancer and is influenced by tumor metabolism. High levels of lactate concentration in the tumor microenvironment as a result of metabolic reprogramming are inversely correlated with patient overall survival. Herein, we investigated the role of lactate in the regulation of the activity of TAZ and showed that glycolysis‐derived lactate efficiently increased TAZ expression and activity in lung cancer cells. We showed that the reactive oxygen species (ROS) generated by lactate‐fueled oxidative phosphorylation (OXPHOS) in mitochondria activated AKT and thereby inhibited glycogen synthase kinase 3 beta/beta‐transducin repeat‐containing proteins (GSK‐3β/β‐TrCP)‐mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1). Upregulation of DNMT1 by lactate caused hypermethylation of TAZ negative regulator of the LATS2 gene promoter, leading to TAZ activation. Moreover, TAZ binds to the promoter of DNMT1 and is necessary for DNMT1 transcription. Our study showed a molecular mechanism of DNMT1 in linking tumor metabolic reprogramming to the Hippo‐TAZ pathway and functional significance of the DNMT1‐TAZ feedback loop in the migratory and invasive potential of lung cancer cells. Glycolysis-derived lactate efficiently increased TAZ expression and activity in lung cancer cells. ROS generated by lactate-fueled OXPHOS in mitochondria activated AKT and thereby inhibited GSK-3β/β-TrCP-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1). Upregulation of DNMT1 caused hypermethylation of the LATS2 gene promoter. TAZ binds to the promoter of DNMT1 and is necessary for DNMT1 transcription.