Notch1/TAZ axis promotes aerobic glycolysis and immune escape in lung cancer

• Published in: Cell death & disease 2021-09, Vol.12 (9), p.832-832, Article 832
• Main Authors: Xie, Mian, Fu, Xin-ge, Jiang, Ke
• Format: Article
• Language: English
• Subjects: 13/109; 13/95; 38/1; 38/22; 631/67; 692/699/67; Aerobiosis; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Cytotoxicity; Feedback, Physiological; Gene expression; Gene Expression Regulation, Neoplastic; Genes, Reporter; Glycolysis; Glycolysis - genetics; Histones; Humans; Immune evasion; Immune Evasion - genetics; Immunology; Immunosurveillance; Invasiveness; Killer Cells, Natural - immunology; Lactic acid; Lactic Acid - metabolism; Life Sciences; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lymphocyte Activation - immunology; Lymphocytes T; Metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Notch1 protein; p300-CBP Transcription Factors - metabolism; Protein Binding; Receptor, Notch1 - metabolism; Serrate-Jagged Proteins - metabolism; Signal Transduction; T-Lymphocytes, Cytotoxic - immunology; TEA Domain Transcription Factors - metabolism; Transcription; Transcriptional Coactivator with PDZ-Binding Motif Proteins - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04124-6

Oncogenic signaling pathway reprograms cancer cell metabolism to promote aerobic glycolysis in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Notch1 signaling, dysregulated in lung cancer, is correlated with increased glycolysis. Herein, we demonstrate in lung cancer that Notch1 promotes glycolytic gene expression through functional interaction with histone acetyltransferases p300 and pCAF. Notch1 signaling forms a positive feedback loop with TAZ. Notch1 transcriptional activity was increased in the presence of TAZ and the activation was TEAD1 independent. Notably, aerobic glycolysis was critical for Notch1/TAZ axis modulation of lung cancer growth in vitro and in vivo. Increased level of extracellular lactate via Notch1/TAZ axis inhibited cytotoxic T-cell activity, leading to the invasive characteristic of lung cancer cells. Interaction between Notch1 and TAZ promoted aerobic glycolysis and immune escape in lung cancer. Our findings provide potential therapeutic targets against Notch1 and TAZ and would be important for clinical translation in lung cancer.