Zinc finger protein 746 promotes colorectal cancer progression via c-Myc stability mediated by glycogen synthase kinase 3β and F-box and WD repeat domain-containing 7
Zinc finger protein 746 promotes colorectal cancer progression via c-Myc stability mediated by glycogen synthase kinase 3β and F-box and WD repeat domain-containing 7
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DOI：
10.1038/s41388-018-0225-0
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发表时间：
2018-07-05
期刊：
影响因子：
8
通讯作者：
Kim, Sung-Hoon
中科院分区：
文献类型：
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作者：
Jung, Ji Hoon;Jung, Deok-Beom;Kim, Sung-Hoon
为了阐明锌指蛋白746（ZNF 746）的潜在致癌机制，本研究在结直肠癌（CRC）中进行。在此，ZNF 746在HCT 116、SW 620和SW 480细胞中过表达，这得到了CRC组织芯片和TCGA分析的支持。DNA微阵列分析显示ZNF 746缺失的HCT 116细胞中与细胞周期相关的基因和c-Myc基因的差异表达。免疫共沉淀和免疫荧光结果表明，ZNF 746通过与c-Myc直接结合而增强c-Myc的稳定性，而ZNF 746和c-Myc主要存在于核浆中。相反，ZNF 746消耗减弱了c-Myc（S62）和糖原合成酶激酶3 β（GSK 3 β）（S9）的磷酸化，也激活了p-c-Myc（T58），这被GSK 3抑制剂如SB-216763和Enza逆转。此外，通过敲低F-box/WD重复蛋白7（FBW 7）泛素连接酶或蛋白酶体抑制剂MG 132，ZNF 746耗竭导致的c-Myc降解被阻断。此外，ZNF 746缺失的HCT 116癌细胞的生长受到抑制，ZNF 746和c-Myc的表达降低。总体而言，这些发现表明ZNF 746通过GSK 3和FBW 7介导的c-Myc稳定性促进CRC进展。
To elucidate the underlying oncogenic mechanism of zinc finger protein 746 (ZNF746), current study was conducted in colorectal cancers (CRCs). Herein, ZNF746 was overexpressed in HCT116, SW620, and SW480 cells, which was supported by CRC tissue microarray and TCGA analysis. Also, DNA microarray revealed the differentially expressed gene profile particularly related to cell cycle genes and c-Myc in ZNF746 depleted HCT116 cells. Furthermore, ZNF746 enhanced the stability of c-Myc via their direct binding through nuclear colocalization by immunoprecipitation and immunofluorescence, while ZNF746 and c-Myc exist mainly in nucleoplasm. Conversely, ZNF746 depletion attenuated phosphorylation of c-Myc (S62) and glycogen synthase kinase 3 beta (GSK3 beta) (S9) and also activated p-c-Myc (T58), which was reversed by GSK3 inhibitors such as SB-216763 and Enza. Also, c-Myc degradation by ZNF746 depletion was blocked by knockdown of F-box/WD repeat-containing protein 7 (FBW7) ubiquitin ligase or proteosomal inhibitor MG132. Additionally, the growth of ZNF746 depleted HCT116 cancer cells was retarded with decreased expression of ZNF746 and c-Myc. Overall, these findings suggest that ZNF746 promotes CRC progression via c-Myc stability mediated by GSK3 and FBW7.