Zhu Zhehui, Ding Rui, Yu Wei, Liu Yun, Zhou Zhaocai, Liu Chen-Ying
Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
Cell Death Differ. 2025 May;32(5):911-925. doi: 10.1038/s41418-025-01446-2. Epub 2025 Jan 28.
Hyperactivation of the YAP/TEAD transcriptional complex in cancers facilitates the development of an immunosuppressive tumor microenvironment. Herein, we observed that the transcription factor SP1 physically interacts with and stabilizes the YAP/TEAD complex at regulatory genomic loci in colorectal cancer (CRC). In response to serum stimulation, PKCζ (protein kinase C ζ) was found to phosphorylate SP1 and enhance its interaction with TEAD4. As a result, SP1 enhanced the transcriptional activity of YAP/TEAD and coregulated the expression of a group of YAP/TEAD target genes. The immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) was identified as a direct target of the SP1-YAP/TEAD4 complex and found to be widely expressed in CRC cells. Importantly, YAP-induced VISTA upregulation in human CRC cells was found to strongly suppress the antitumor function of CD8 T cells. Consistently, elevated VISTA expression was found to be correlated with hyperactivation of the SP1-YAP/TEAD axis and associated with poor prognosis of CRC patients. In addition, we found by serendipity that enzymatic deglycosylation significantly improved the anti-VISTA antibody signal intensity, resulting in more accurate detection of VISTA in clinical tumor samples. Overall, our study identified SP1 as a positive modulator of YAP/TEAD for the transcriptional regulation of VISTA and developed a protein deglycosylation strategy to better detect VISTA expression in clinical samples. These findings revealed a new tumor cell-intrinsic mechanism of YAP/TAZ-mediated cancer immune evasion.
YAP/TEAD转录复合物在癌症中的过度激活促进了免疫抑制性肿瘤微环境的形成。在此，我们观察到转录因子SP1在结直肠癌（CRC）的调控基因组位点与YAP/TEAD复合物发生物理相互作用并使其稳定。在血清刺激下，发现蛋白激酶Cζ（PKCζ）使SP1磷酸化并增强其与TEAD4的相互作用。结果，SP1增强了YAP/TEAD的转录活性，并共同调节一组YAP/TEAD靶基因的表达。免疫检查点T细胞激活V结构域Ig抑制因子（VISTA）被鉴定为SP1-YAP/TEAD4复合物的直接靶标，并发现其在CRC细胞中广泛表达。重要的是，发现YAP诱导的人CRC细胞中VISTA上调强烈抑制CD8 T细胞的抗肿瘤功能。一致地，发现VISTA表达升高与SP1-YAP/TEAD轴的过度激活相关，并与CRC患者的不良预后相关。此外，我们偶然发现酶促去糖基化显著提高了抗VISTA抗体的信号强度，从而在临床肿瘤样本中更准确地检测VISTA。总体而言，我们的研究确定SP1是YAP/TEAD对VISTA进行转录调控的正向调节因子，并开发了一种蛋白质去糖基化策略以更好地检测临床样本中的VISTA表达。这些发现揭示了YAP/TAZ介导的癌症免疫逃逸的一种新的肿瘤细胞内在机制。
