Department of Medicine, Computational Biomedicine Section, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
Bioinformatics Program, Boston University, 72 East Concord Street, Boston, MA, 02215, USA.
J Exp Clin Cancer Res. 2023 May 8;42(1):116. doi: 10.1186/s13046-023-02674-5.
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.
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.
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.
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.
支气管癌前病变（PML）主要由气道基底上皮细胞相似的细胞组成，这些细胞通过尚未完全阐明的机制具有发展为肺鳞状细胞癌（LUSC）的潜能。尽管目前已经在支气管 PML 病变中对基因表达和细胞多样性进行了映射，但驱动恶性肿瘤的信号和转录事件仍知之甚少。有证据表明 Hippo 通路效应物 YAP 和 TAZ 及其相关的 TEAD 和 TP63 转录因子家族在支气管基底细胞生物学和 LUSC 中具有关键作用。在这项研究中，我们研究了 YAP/TAZ、TEAD 和 TP63 在支气管上皮细胞和 PML 中的功能关联。
我们通过小干扰 RNA（siRNA）介导的 YAP/TAZ、TEAD 或 TP63 耗竭，在原代人支气管上皮细胞中进行了 RNA-seq，并将这些数据与这些因子的 ChIP-seq 分析相结合。鉴定了直接激活或抑制的基因，并在从进展性或退行性人 PML 和肺单细胞 RNA-seq 数据集中获得的基因表达数据中对重叠基因进行了分析。
分析 YAP/TAZ、TEAD 和 TP63 调节的基因在人支气管上皮细胞中的表达，发现了一个强烈与支气管 PML 病理进展相关的收敛转录网络。我们的观察表明，YAP/TAZ-TEAD-TP63 联合作用以协同促进基底上皮细胞增殖，并抑制与干扰素反应和免疫细胞通讯相关的信号。我们鉴定的直接受抑制的靶标包括 MHC II 类转录激活物 CIITA，其在进展性 PML 中受到抑制，并与肺中的适应性免疫反应相关。我们的研究结果为控制驱动 PML 进展的基因表达事件提供了分子见解，包括那些有助于免疫逃逸的事件，为肺癌的干预提供了新的潜在途径。
我们的研究确定了 YAP/TAZ-TEAD-TP63 在肺癌发展早期的重要基因调控功能，其中包括免疫抑制作用，并表明评估该转录复合物的活性可能提供一种识别免疫逃避性支气管 PML 的方法，并可能成为潜在的治疗靶点。
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