Mechanistic insights into kidney cancer Many clear cell renal cell carcinomas (ccRCCs) have alterations to the gene encoding the von Hippel-Lindau protein (VHL). VHL is a ubiquitin ligase that degrades target proteins when they are prolyl-hydroxylated. Zhang et al. performed a genome-wide search for VHL target (see the Perspective by Sanchez and Simon). They identified ZHX2, a protein with structural motifs that indicate DNA binding. ZHX2 has been implicated in tumor suppression. Loss of ZHX2 inhibited signaling through the transcription factor NF-κB, and ZHX2 bound to many NF-κB target genes. Depletion of ZHX2 slowed growth of ccRCC cells in vitro and in a mouse model. Science, this issue p. 290; see also p. 226 A ubiquitin ligase–regulated transcription factor activated in kidney cancer is identified. Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.

中文翻译：

---

VHL底物转录因子ZHX2作为透明细胞肾细胞癌的致癌驱动因子

对肾癌的机制洞察 许多透明细胞肾细胞癌 (ccRCC) 的编码 von Hippel-Lindau 蛋白 (VHL) 的基因发生了改变。VHL 是一种泛素连接酶，当靶蛋白被脯氨酰羟基化时会降解它们。张等人。对 VHL 目标进行了全基因组搜索（参见 Sanchez 和 Simon 的观点）。他们鉴定了 ZHX2，这是一种具有指示 DNA 结合的结构基序的蛋白质。ZHX2 与肿瘤抑制有关。ZHX2 的缺失抑制了通过转录因子 NF-κB 的信号传导，并且 ZHX2 与许多 NF-κB 靶基因结合。ZHX2 的消耗减慢了体外和小鼠模型中 ccRCC 细胞的生长。科学，这个问题 p。290; 另见第。226 鉴定了在肾癌中激活的泛素连接酶调节的转录因子。von Hippel-Lindau (VHL) E3 泛素连接酶蛋白失活是透明细胞肾细胞癌 (ccRCC) 的标志。确定受 VHL 丢失影响的通路如何导致 ccRCC 仍然具有挑战性。我们使用全基因组体外表达策略来鉴定羟基化时结合 VHL 的蛋白质。锌指和同源框 2 (ZHX2) 被发现是 VHL 的靶标，其羟基化使 VHL 能够调节其蛋白质稳定性。来自具有 VHL 功能缺失突变的 ccRCC 患者的肿瘤细胞通常具有增加的 ZHX2 丰度和核定位。在功能上，ZHX2 的消耗在体外和体内抑制了 VHL 缺陷的 ccRCC 细胞生长。从机制上讲，整合染色质免疫沉淀测序和微阵列分析表明 ZHX2 促进核因子 κB 活化。