The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer
The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer
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DOI：
10.1016/j.jbc.2023.103012
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发表时间：
2023-03-31
影响因子：
4.8
通讯作者：
Liu, Chen-Ying
中科院分区：
文献类型：
--
作者：
Song, Jinglue;Dang, Xuening;Liu, Chen-Ying
分泌的胶原蛋白和钙结合EGF结构域1（CCBE 1）通过其在成熟血管内皮生长因子C（VEGFC）的蛋白水解激活中的作用对胚胎淋巴管发育至关重要。我们之前报道过CCBE 1在结直肠癌（CRC）中过表达，并且其转录受到TGF β-SMAD途径的负调节，但CCBE 1在CRC中的转录激活机制仍不清楚。最近的研究揭示了hippo效应子雅普/ TAZ在淋巴管发育中的重要作用;然而，雅普/TAZ在肿瘤淋巴管生成中的作用尚未阐明。在这项研究中，我们发现转录因子TEAD 4的核高表达与结直肠癌患者的淋巴结转移和高淋巴管密度相关。雅普/TAZ-TEAD 4复合物通过直接结合CRC细胞和癌症相关成纤维细胞中的CCBE 1的增强子区域来转录上调CCBE 1的表达，这导致增强的VEGFC蛋白水解并诱导体外人淋巴管内皮细胞的管形成和迁移以及体内CRC细胞衍生的异种移植物模型中的淋巴管生成。此外，布罗莫结构域和额外末端结构域（BET）抑制剂JQ 1在体外和体内显著抑制CCBE 1的转录，抑制VEGFC蛋白水解，并抑制肿瘤淋巴管生成。总之，我们的研究揭示了CCBE 1通过雅普/TAZ-TEAD 4-BRD 4复合物在CRC中的一种新的正性转录调控机制，揭示了雅普/TAZ的促肿瘤淋巴管生成作用以及BET抑制剂对肿瘤淋巴管生成的潜在抑制作用。
The secreted protein collagen and calcium-binding EGF domain 1 (CCBE1) is critical for embryonic lymphatic devel-opment through its role in the proteolytic activation of mature vascular endothelial growth factor C (VEGFC). We previously reported that CCBE1 is overexpressed in colorectal cancer (CRC) and that its transcription is negatively regulated by the TGF beta-SMAD pathway, but the transcriptional activation mechanism of CCBE1 in CRC remains unknown. Recent studies have revealed the vital role of the hippo effectors YAP/ TAZ in lymphatic development; however, the role of YAP/TAZ in tumor lymphangiogenesis has not been clarified. In this study, we found that high nuclear expression of transcription factor TEAD4 is associated with lymph node metastasis and high lymphatic vessel density in patients with CRC. YAP/TAZ- TEAD4 complexes transcriptionally upregulated the expression of CCBE1 by directly binding to the enhancer region of CCBE1 in both CRC cells and cancer-associated fibroblasts, which resulted in enhanced VEGFC proteolysis and induced tube formation and migration of human lymphatic endothelial cells in vitro and lymphangiogenesis in a CRC cell-derived xenograft model in vivo. In addition, the bromodomain and extra -terminal domain (BET) inhibitor JQ1 significantly inhibited the transcription of CCBE1, suppressed VEGFC proteolysis, and inhibited tumor lymphangiogenesis in vitro and in vivo. Collectively, our study reveals a new positive transcriptional regulatory mechanism of CCBE1 via YAP/TAZ-TEAD4-BRD4 complexes in CRC, which exposes the protumor lymphangio-genic role of YAP/TAZ and the potential inhibitory effect of BET inhibitors on tumor lymphangiogenesis.