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

Abstract

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.

• Authors: Mian Xie, Xin-Ge Fu, Ke Jiang
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 9 Pg. 832 (09 04 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 34482375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Receptor, Notch1
• Serrate-Jagged Proteins
• TEA Domain Transcription Factors
• TEAD1 protein, human
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• WWTR1 protein, human
• Lactic Acid
• p300-CBP Transcription Factors
• p300-CBP-associated factor

Topics

• Aerobiosis
• Animals
• Cell Line, Tumor
• Feedback, Physiological
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Glycolysis (genetics)
• Humans
• Immune Evasion (genetics)
• Killer Cells, Natural (immunology)
• Lactic Acid (metabolism)
• Lung Neoplasms (genetics, immunology, metabolism)
• Lymphocyte Activation (immunology)
• Mice, Inbred BALB C
• Mice, Nude
• Models, Biological
• Protein Binding
• Receptor, Notch1 (metabolism)
• Serrate-Jagged Proteins (metabolism)
• Signal Transduction
• T-Lymphocytes, Cytotoxic (immunology)
• TEA Domain Transcription Factors (metabolism)
• Transcriptional Coactivator with PDZ-Binding Motif Proteins (metabolism)
• p300-CBP Transcription Factors (metabolism)