Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.
Department of Anatomic pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.
Cancer Res Commun. 2022 Jul;2(7):624-638. doi: 10.1158/2767-9764.crc-21-0084. Epub 2022 Jul 12.
The transcriptional co-activator YAP1 is the major oncogenic component of the Hippo signaling pathway and contributes to the genesis and progression of various tumors, including non-small cell lung cancer (NSCLC). YAP1 levels are regulated by the canonical Hippo kinases, MST1/2 and LATS1/2, which modulate its cytoplasmic retention and proteasomal degradation. While non-canonical regulation of YAP1 has been reported, its role in hypoxic response is not fully elucidated. The studies presented here show that YAP1 levels and function are modulated by VHL and PHD2. YAP1 could regulate multiple genes involved in angiogenesis through E2F1; it also associates with HIF1α in cancer cells under hypoxic conditions, inducing the VEGF-A promoter. Under normoxic conditions, PHD2 associates with and hydroxylates specific proline residues on YAP1, facilitating its interaction with VHL and promoting ubiquitination and subsequent proteasomal degradation. Exposure to hypoxia dissociates YAP1 from PHD2 and VHL, elevating YAP1 levels and enhancing its association with HIF1α. YAP1-HIF1α interaction was higher in NSCLC and RCC samples, indicating a role for this interaction in the genesis of these cancers. Our results thus reveal a novel mode of regulation of YAP1 by PHD2 and VHL in normoxic cells, suggesting that YAP1-mediated induction of VEGF and other genes contributes to hypoxic response in tumors.
转录共激活因子 YAP1 是 Hippo 信号通路的主要致癌成分，有助于各种肿瘤的发生和发展，包括非小细胞肺癌（NSCLC）。YAP1 水平受经典 Hippo 激酶 MST1/2 和 LATS1/2 调节，这些激酶调节其细胞质保留和蛋白酶体降解。虽然已经报道了 YAP1 的非经典调节，但它在低氧反应中的作用尚未完全阐明。本研究表明，YAP1 的水平和功能受 VHL 和 PHD2 调节。YAP1 可以通过 E2F1 调节参与血管生成的多个基因；它还在缺氧条件下与癌细胞中的 HIF1α 结合，诱导 VEGF-A 启动子。在常氧条件下，PHD2 与 YAP1 上的特定脯氨酸残基结合并羟基化，促进其与 VHL 的相互作用，并促进泛素化和随后的蛋白酶体降解。缺氧会使 YAP1 与 PHD2 和 VHL 分离，从而提高 YAP1 水平并增强其与 HIF1α 的结合。在 NSCLC 和 RCC 样本中，YAP1-HIF1α 相互作用更高，表明这种相互作用在这些癌症的发生中起作用。我们的结果因此揭示了 PHD2 和 VHL 在常氧细胞中对 YAP1 的一种新的调节模式，表明 YAP1 介导的 VEGF 和其他基因的诱导有助于肿瘤的低氧反应。
