ZNF774 是一种有效的肝癌发生抑制剂，通过抑制 NOTCH2 信号传导。,Oncogene

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ZNF774 是一种有效的肝癌发生抑制剂，通过抑制 NOTCH2 信号传导。
Oncogene ( IF 6.9 ) Pub Date : 2019-10-28 , DOI: 10.1038/s41388-019-1075-0
Chengjian Guan _{1,

2,

3} , Lin He ₄ , Zhenyu Chang _{2,

3} , Xinjin Gu _{2,

3} , Jing Liang ₄ , Rong Liu _{2,

3}

Affiliation

从乘客中辨别致癌驱动因素仍然是了解肝细胞癌 (HCC) 发生和发展本质的主要努力，肝细胞癌是最常见的原发性肝脏恶性肿瘤，也是全球癌症死亡的第三大原因。在这里，我们报道 ZNF774 是一种新型锌指蛋白，可抑制 HCC 细胞的增殖和侵袭。该蛋白的分子表征表明 ZNF774 充当转录抑制因子，通过亲和纯化耦合质谱对 ZNF774 相互作用组的询问表明 ZNF774 与细胞中的 Mi-2/核小体重塑和去乙酰化酶 (NuRD) 复合物物理相关。通过 ChIP-seq 对 ZNF774/NuRD 复合物转录靶点的全基因组鉴定表明，ZNF774 抑制了包括 NOTCH2 在内的一组基因，这些基因与 HCC 的生长和迁移率密切相关。我们证明了 ZNF774/NuRD 复合物在体外抑制 HCC 细胞的增殖和侵袭，并在体内抑制 HCC 生长和转移。重要的是，ZNF774 的表达在 HCC 中显着下调，并且低 ZNF774 表达与高 NOTCH2 表达、晚期病理阶段和患者总生存期差密切相关。总之，这些结果揭示了 ZNF774/NuRD-NOTCH2 轴在肝癌发生中的关键作用。我们证明了 ZNF774/NuRD 复合物在体外抑制 HCC 细胞的增殖和侵袭，并在体内抑制 HCC 生长和转移。重要的是，ZNF774 的表达在 HCC 中显着下调，并且低 ZNF774 表达与高 NOTCH2 表达、晚期病理阶段和患者总生存期差密切相关。总之，这些结果揭示了 ZNF774/NuRD-NOTCH2 轴在肝癌发生中的关键作用。我们证明了 ZNF774/NuRD 复合物在体外抑制 HCC 细胞的增殖和侵袭，并在体内抑制 HCC 生长和转移。重要的是，ZNF774 的表达在 HCC 中显着下调，并且低 ZNF774 表达与高 NOTCH2 表达、晚期病理阶段和患者总生存期差密切相关。总之，这些结果揭示了 ZNF774/NuRD-NOTCH2 轴在肝癌发生中的关键作用。

"点击查看英文标题和摘要"

ZNF774 is a potent suppressor of hepatocarcinogenesis through dampening the NOTCH2 signaling.

Discerning oncogenic drivers from passengers remain a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), which is the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. Genome-wide identification of the transcriptional targets of the ZNF774/NuRD complex by ChIP-seq indicated that ZNF774 represses a cohort of genes including NOTCH2 that are critically involved in the growth and mobility of HCC. We demonstrated that the ZNF774/NuRD complex inhibits the proliferation and invasion of HCC cells in vitro and suppresses HCC growth and metastasis in vivo. Importantly, the expression of ZNF774 is significantly downregulated in HCC, and low ZNF774 expression strongly correlated with high NOTCH2 expression, advanced pathological stages, and poor overall survival of the patients. Together, these results uncover a key role for the ZNF774/NuRD-NOTCH2 axis in hepatocarcinogenesis.

更新日期：2019-10-28

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