Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, Canada.
Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Canada.
Cancer Res Commun. 2024 Sep 1;4(9):2374-2383. doi: 10.1158/2767-9764.CRC-24-0101.
Opposite expression and pro- or anti-cancer function of YAP and its paralog TAZ/WWTR1 stratify cancers into binary YAPon and YAPoff classes. These transcriptional coactivators are oncogenic in YAPon cancers. In contrast, YAP/TAZ are silenced epigenetically along with their integrin and extracellular matrix adhesion target genes in neural and neuroendocrine YAPoff cancers (e.g., small cell lung cancer, retinoblastoma). Forced YAP/TAZ expression induces these targets, causing cytostasis in part through Integrin-αV/β5, independent of the integrin-binding RGD ligand. Other effectors of this anticancer YAP function are unknown. Here, using clustered regularly interspaced short palindromic repeats (CRISPR) screens, we link the Netrin receptor UNC5B to YAP-induced cytostasis in YAPoff cancers. Forced YAP expression induces UNC5B through TEAD DNA-binding partners, as either TEAD1/4-loss or a YAP mutation that disrupts TEAD-binding (S94A) blocks, whereas a TEAD-activator fusion (TEAD(DBD)-VP64) promotes UNC5B induction. Ectopic YAP expression also upregulates UNC5B relatives and their netrin ligands in YAPoff cancers. Netrins are considered protumorigenic, but knockout and peptide/decoy receptor blocking assays reveal that in YAPoff cancers, UNC5B and Netrin-1 can cooperate with integrin-αV/β5 to mediate YAP-induced cytostasis. These data pinpoint an unsuspected Netrin-1/UNC5B/integrin-αV/β5 axis as a critical effector of YAP tumor suppressor activity.
Netrins are widely perceived as procancer proteins; however, we uncover an anticancer function for Netrin-1 and its receptor UNC5B.
YAP 及其同源物 TAZ/WWTR1 的相反表达和促癌或抑癌功能将癌症分为 YAPon 和 YAPoff 两类。这些转录共激活因子在 YAPon 癌症中是致癌的。相比之下，在神经和神经内分泌 YAPoff 癌症（如小细胞肺癌、视网膜母细胞瘤）中，YAP/TAZ 被表观遗传沉默，与其整合素和细胞外基质黏附靶基因一起沉默。强制表达 YAP/TAZ 会诱导这些靶基因，部分通过整合素-αV/β5 引起细胞停滞，而不依赖整合素结合的 RGD 配体。这种抗癌 YAP 功能的其他效应子尚不清楚。在这里，我们使用成簇规律间隔短回文重复（CRISPR）筛选将神经导向因子受体 UNC5B 与 YAPoff 癌症中的 YAP 诱导细胞停滞联系起来。强制表达 YAP 通过 TEAD DNA 结合伴侣诱导 UNC5B，因为 TEAD1/4 缺失或破坏 TEAD 结合（S94A）的 YAP 突变会阻止 UNC5B 的诱导，而 TEAD 激活剂融合（TEAD（DBD）-VP64）则促进 UNC5B 的诱导。异位表达 YAP 也在上调 YAPoff 癌症中的 UNC5B 及其神经导向因子配体。神经导向因子被认为是致癌的，但敲除和肽/诱饵受体阻断试验表明，在 YAPoff 癌症中，UNC5B 和神经导向因子-1 可以与整合素-αV/β5 合作介导 YAP 诱导的细胞停滞。这些数据确定了一个意想不到的神经导向因子-1/UNC5B/整合素-αV/β5 轴作为 YAP 肿瘤抑制活性的关键效应子。
神经导向因子被广泛认为是促癌蛋白；然而，我们发现神经导向因子-1 和其受体 UNC5B 具有抗癌功能。
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