通常认为 Hippo 途径通过磷酸化转录辅助因子 YAP 将其隔离在细胞质中并减少 YAP-TEAD 转录复合物的形成来抑制肿瘤生长。 YAP 的异常激活发生在多种癌症中。然而，我们发现 YAP 在透明细胞肾细胞癌 (ccRCC) 中具有肿瘤抑制功能。使用细胞培养物、异种移植物和患者来源的外植体模型，我们发现上游 Hippo 通路激酶 MST1 和 MST2 的抑制或组成型活性 YAP 突变体的表达会阻碍 ccRCC 增殖并减少转录因子 NF-κB 介导的基因表达。从机制上讲，NF-κB 亚基 p65 与转录辅助因子 TEAD 结合，促进 NF-κB 靶基因表达，从而促进细胞增殖。然而，通过竞争 TEAD，YAP 破坏了其与 NF-κB 的相互作用，并促使 p65 从靶基因启动子上解离，从而抑制 NF-κB 转录程序。 ccRCC 中 Hippo 和 NF-κB 通路之间的这种串扰表明，以非典型方式（即通过激活 YAP）靶向 Hippo-YAP 轴可能是减缓患者肿瘤生长的策略。

The Hippo pathway is generally understood to inhibit tumor growth by phosphorylating the transcriptional cofactor YAP to sequester it to the cytoplasm and reduce the formation of YAP-TEAD transcriptional complexes. Aberrant activation of YAP occurs in various cancers. However, we found a tumor-suppressive function of YAP in clear cell renal cell carcinoma (ccRCC). Using cell cultures, xenografts, and patient-derived explant models, we found that the inhibition of upstream Hippo-pathway kinases MST1 and MST2 or expression of a constitutively active YAP mutant impeded ccRCC proliferation and decreased gene expression mediated by the transcription factor NF-κB. Mechanistically, the NF-κB subunit p65 bound to the transcriptional cofactor TEAD to facilitate NF-κB-target gene expression that promoted cell proliferation. However, by competing for TEAD, YAP disrupted its interaction with NF-κB and prompted the dissociation of p65 from target gene promoters, thereby inhibiting NF-κB transcriptional programs. This cross-talk between the Hippo and NF-κB pathways in ccRCC suggests that targeting the Hippo-YAP axis in an atypical manner-that is, by activating YAP-may be a strategy for slowing tumor growth in patients.