A Novel PHD2/VHL-mediated Regulation of YAP1 Contributes to VEGF Expression and Angiogenesis.
A Novel PHD2/VHL-mediated Regulation of YAP1 Contributes to VEGF Expression and Angiogenesis.
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一种新型的由PHD2/VHL介导的YAP1调控有助于VEGF表达和血管生成。
DOI：
10.1158/2767-9764.crc-21-0084
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Chellappan, Srikumar
中科院分区：
文献类型：
--
作者：
Bora-Singhal, Namrata;Saha, Biswarup;Mohankumar, Durairaj;Padmanabhan, Jaya;Coppola, Domenico;Chellappan, Srikumar
转录共激活因子YAP1是Hippo信号通路的主要致癌成分，并促进包括非小细胞肺癌（NSCLC）在内的多种肿瘤的发生和进展。YAP1的水平受经典的Hippo激酶MST1/2和LATS1/2调控，这些激酶调节其胞质滞留和蛋白酶体降解。虽然已有关于YAP1非经典调控的报道，但其在缺氧反应中的作用尚未完全阐明。本文的研究表明，YAP1的水平和功能受VHL和PHD2调节。YAP1可通过E2F1调控多个参与血管生成的基因；在缺氧条件下，它还与癌细胞中的HIF1α结合，诱导VEGF - A启动子。在常氧条件下，PHD2与YAP1结合并羟基化其特定的脯氨酸残基，促进其与VHL的相互作用，推动泛素化及随后的蛋白酶体降解。暴露于缺氧环境会使YAP1与PHD2和VHL解离，提高YAP1水平并增强其与HIF1α的结合。YAP1 - HIF1α的相互作用在NSCLC和肾细胞癌（RCC）样本中更强，表明这种相互作用在这些癌症的发生中起作用。因此，我们的结果揭示了常氧细胞中PHD2和VHL对YAP1的一种新型调控模式，提示YAP1介导的VEGF和其他基因的诱导有助于肿瘤的缺氧反应。
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.
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