Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
J Invest Dermatol. 2022 Jan;142(1):65-76.e7. doi: 10.1016/j.jid.2021.06.020. Epub 2021 Jul 20.
Disruption of the transcriptional activity of the Hippo pathway members YAP1 and TAZ has become a major target for cancer treatment. However, detailed analysis of the effectiveness and networks affected by YAP1/TAZ transcriptional targeting is limited. In this study, we utilize TEAD inhibitor, an inhibitor of the binding of YAP1 and TAZ with their main transcriptional target TEAD in a mouse model of basal cell carcinoma, to unveil the consequences of YAP1/TAZ transcriptional blockage in cancer cells. Both TEAD inhibitor and YAP1/TAZ knockdown lead to reduced proliferation and increased differentiation of mouse basal cell carcinoma driven by oncogenic hedgehog-smoothened (SmoM2) activity. Although TEAD-transcriptional networks were essential to inactivate differentiation, this inactivation was found to be indirect and potentially mediated through the repression of KLF4 by SNAI2. By comparing the transcriptional effects of TEAD inhibition with those caused by YAP1/TAZ depletion, we determined YAP1/TAZ‒TEAD‒independent effects in cancer cells that impact STAT3 and NF-κB. Our results reveal the gene networks affected by targeting YAP1/TAZ‒TEAD in basal cell carcinoma tumors and expose the potential pitfalls for targeting TEAD transcription in cancer.
阻断 Hippo 通路成员 YAP1 和 TAZ 的转录活性已成为癌症治疗的主要靶点。然而，对 YAP1/TAZ 转录靶向的有效性和受影响网络的详细分析受到限制。在这项研究中，我们利用 TEAD 抑制剂，即 YAP1 和 TAZ 与其主要转录靶标 TEAD 结合的抑制剂，在基底细胞癌的小鼠模型中，揭示了 YAP1/TAZ 转录阻断在癌细胞中的后果。TEAD 抑制剂和 YAP1/TAZ 敲低均导致由致癌 Hedgehog- smoothened (SmoM2) 活性驱动的小鼠基底细胞癌的增殖减少和分化增加。尽管 TEAD 转录网络对于失活分化至关重要，但这种失活被发现是间接的，可能是通过 SNAI2 对 KLF4 的抑制介导的。通过比较 TEAD 抑制和 YAP1/TAZ 耗竭引起的转录效应，我们确定了在癌症细胞中影响 STAT3 和 NF-κB 的 YAP1/TAZ-TEAD 独立效应。我们的研究结果揭示了靶向基底细胞癌肿瘤中 YAP1/TAZ-TEAD 所影响的基因网络，并揭示了在癌症中靶向 TEAD 转录的潜在陷阱。
