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

Abstract

Background Bronchial 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. Methods We 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. Results Analysis 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. Conclusions Our 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.

The Reign of Follistatin in Tumors and Their Microenvironment: Implications for Drug Resistance

“…Intriguingly, YAP1 also functions as a coregulator in an immune evasion program orchestrated by TEAD/p63 within airway basal epithelial cells, where FST serves as a target gene [146]. These findings, along with the positive association between increased FST expression in HNSCC and tumor-infiltrating immunosuppressive cells as reported by our group [126], further support the role of transcriptional cross-talk that acts upstream of FST in fostering an immune-evasive TME (Figures 3B and 6).…”

Influence of intersignaling crosstalk on the intracellular localization of YAP/TAZ in lung cells

“…In response to S. pneumoniae strain T4 (SpT4) lung infection, YAP/TAZ is activated in AT2 cells, and YAP/TAZ deletion in AT2 cells impairs alveolar epithelial regeneration and promotes fibrosis [ 42 ]. In addition, nuclear YAP/TAZ bound to TEAD transcription factors can bind to the TP63 factor and form a YAP/TAZ-TEAD-TP63 complex, which downregulates genes associated with early immune evasion and contributes to lung carcinogenesis, as has been shown in human bronchial cells [ 43 ].…”

SIRPG promotes lung squamous cell carcinoma pathogenesis via M1 macrophages: a multi-omics study integrating data and Mendelian randomization

“…Importantly, they satisfy the three fundamental assumptions of MR: the relevance assumption, independence assumption, and exclusion restriction assumption ( 22 ). There have been numerous studies focusing on multi-omics sequencing analysis of lung adenocarcinoma ( 23 , 24 ). However, it has been challenging to analyze the etiology of LUSC from an epidemiological perspective.…”