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

Mian Xie,Ke Jiang,Xin-Ge Fu

doi:10.1038/s41419-021-04124-6

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.

Highlights

Notch signaling exerts oncogenic and tumor-suppressive effects during tumorigenesis
The results indicate that glycolysis mediated by Notch1/transcriptional coactivator with PDZ-binding motif (TAZ) axis is critical for lung cancer growth
Our study indicates that p300-mediated H4K5ac and p300/CBP-associated factor (pCAF)-mediated H3K9ac are essential for the Notch1 regulation of glycolytic genes (LDHA, PKM2, PFKB3, PKM2, HK2, GLUT1, and ALDOA). pCAF is a co-factor shared between p53 and HIF-1 in the regulation of glycolytic production by modulating SCO2 and TIGAR gene expression [29]. p300 functions as a lysine 2-hyroxyisobutyryltransferase to regulate glycolysis in response to nutritional cues

Summary

Introduction

Notch signaling exerts oncogenic and tumor-suppressive effects during tumorigenesis. In human, there are four Notch receptors (Notch 1–4) that, upon interaction with Notch ligand DLL1, DLL3, DLL4, Jagged, and Jagged, are proteolytically cleaved to release Notch intracellular domain (Notch ICD), which translocates into the nucleus to regulate the expressions of target genes, including Hes1 [1]. Our previous study shows that Notch overexpression is associated with drug resistance in non-small cell lung cancer (NSCLC) [2]. Notch co-expression is distinctly enriched for pathways associated with angiogenesis and vascular development, immune system, and Rho GTPase activity [3]. Notch is involved in the innate immune system and Notch knockdown in lung cancer enhances innate immune recruitment [4]. Recent study shows that tumor metabolic dysregulation sensitizes cancer cells to antitumor immune cells implying that Notch-associated metabolic phenotype and immune escape harmonize during cancer progression [5]. Lung cancers demonstrate enhanced aerobic glycolysis and microenvironmental acidity [6]. Tumor acidity is a key regulator of cancer immunity that orchestrates immunosuppression [7]

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Results

Conclusion