Convergence of YAP/TAZ, TEAD and TP63 activity is associated with bronchial premalignant severity and progression

Journal of Experimental & Clinical Cancer Research

Research

Adeline Matschulat¹  Xaralabos Varelas¹  Andrew M. Tilston-Lunel¹  Julia Hicks-Berthet¹  Justice Simonetti¹  Marc E. Lenburg²  Roxana Pfefferkorn²  Boting Ning²  Jennifer E. Beane²  Sarah Mazzilli²  Avrum Spira³  Matthew Edwards⁴ 

[1] Department of Biochemistry and Cell Biology, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord Street, Room K620, 02118, Boston, MA, USA;Department of Medicine, Computational Biomedicine Section, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord Street, 02118, Boston, MA, USA;Bioinformatics Program, Boston University, 72 East Concord Street, 02215, Boston, MA, USA;Department of Medicine, Computational Biomedicine Section, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord Street, 02118, Boston, MA, USA;Johnson and Johnson Innovation, 02142, Cambridge, MA, USA;Johnson and Johnson Innovation, 02142, Cambridge, MA, USA;

关键词: Bronchial premalignant lesions;    YAP;    TAZ;    TEAD;    TP63;    Immune evasion;    CIITA;    MHCII;   

DOI  :  10.1186/s13046-023-02674-5

 received in 2022-12-17, accepted in 2023-04-12,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundBronchial premalignant lesions (PMLs) are composed primarily of cells resembling basal epithelial cells of the airways, which through poorly understood mechanisms have the potential to progress to lung squamous cell carcinoma (LUSC). Despite ongoing efforts that have mapped gene expression and cell diversity across bronchial PML pathologies, signaling and transcriptional events driving malignancy are poorly understood. Evidence has suggested key roles for the Hippo pathway effectors YAP and TAZ and associated TEAD and TP63 transcription factor families in bronchial basal cell biology and LUSC. In this study we examine the functional association of YAP/TAZ, TEADs and TP63 in bronchial epithelial cells and PMLs.MethodsWe performed RNA-seq in primary human bronchial epithelial cells following small interfering RNA (siRNA)-mediated depletion of YAP/TAZ, TEADs or TP63, and combined these data with ChIP-seq analysis of these factors. Directly activated or repressed genes were identified and overlapping genes were profiled across gene expression data obtained from progressive or regressive human PMLs and across lung single cell RNA-seq data sets.ResultsAnalysis of genes regulated by YAP/TAZ, TEADs, and TP63 in human bronchial epithelial cells revealed a converged transcriptional network that is strongly associated with the pathological progression of bronchial PMLs. Our observations suggest that YAP/TAZ-TEAD-TP63 associate to cooperatively promote basal epithelial cell proliferation and repress signals associated with interferon responses and immune cell communication. Directly repressed targets we identified include the MHC Class II transactivator CIITA, which is repressed in progressive PMLs and associates with adaptive immune responses in the lung. Our findings provide molecular insight into the control of gene expression events driving PML progression, including those contributing to immune evasion, offering potential new avenues for lung cancer interception.ConclusionsOur study identifies important gene regulatory functions for YAP/TAZ-TEAD-TP63 in the early stages of lung cancer development, which notably includes immune-suppressive roles, and suggest that an assessment of the activity of this transcriptional complex may offer a means to identify immune evasive bronchial PMLs and serve as a potential therapeutic target.

【 授权许可】

CC BY   
© The Author(s) 2023

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