ZNF191 alters DNA methylation and activates the PI3K-AKT pathway in hepatoma cells via transcriptional regulation of DNMT1.
ZNF191 alters DNA methylation and activates the PI3K-AKT pathway in hepatoma cells via transcriptional regulation of DNMT1.
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ZNF191 通过 DNMT1 的转录调节改变 DNA 甲基化并激活肝癌细胞中的 PI3K-AKT 通路
DOI：
10.1002/cam4.4535
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发表时间：
2022-03
期刊：
影响因子：
4
通讯作者：
Liu G
中科院分区：
文献类型：
--
作者：
Liu Y;Cheng H;Cheng C;Zheng F;Zhao Z;Chen Q;Zeng W;Zhang P;Huang C;Jiang W;Liu X;Liu G
DNA甲基化改变是肝细胞癌发生发展过程中的重要事件。DNA甲基转移酶(DNMT)1是DNA甲基化机制的最主要贡献者，在肝细胞癌中显著升高，并与不良预后显著相关。然而，DNMT1在肝细胞癌中的转录调控仍不清楚。采用实时荧光定量聚合酶链式反应和免疫组织化学方法检测肝癌组织中DNMT1和锌指转录因子191(ZNF191)的表达。用荧光素酶报告活性实验分析DNMT1启动子的转录活性。用染色质免疫沉淀法和凝胶电泳法检测ZNF191蛋白与DNMT1启动子的结合能力。用甲基化芯片检测肝癌细胞DNA甲基化水平。ZNF191能正向调控DNMT1基因的表达，提高DNMT1启动子的转录活性。芯片定量聚合酶链式反应和EMSA分析表明，ZNF191蛋白在NT-240 AT(TCAT)3TC处直接与DNMT1启动子结合。此外，DNMT1和ZNF191在人肝细胞癌中的表达呈正相关。利用甲基化芯片观察到ZNF191基因敲除的肝癌细胞DNA甲基化改变，差异甲基化位点在PI3K-AKT途径中丰富。此外，我们还证实了DNMT1通过PI3K-AKT途径参与了ZNF191对肝癌细胞生长的影响。ZNF191是一种新的DNMT1转录调节因子，ZNF191/DNMT1/p-AKT轴在肝癌细胞中的促增殖作用提示，ZNF191在肝癌细胞中的状态可能会影响DNMTS抑制剂和PI3K抑制剂的疗效，从而达到精确治疗肝癌的目的。ZNF191直接与DNMT1启动子结合，反式激活DNMT1基因。ZNF191改变PI3K-AKT途径富含DMS的肝癌细胞DNA甲基化。DNMT1通过PI3K-AKT途径参与ZNF191对肝癌细胞生长的影响。
Alteration of DNA methylation is an important event in pathogenesis and progression of hepatocellular carcinoma (HCC). DNA methyltransferase (DNMT) 1, the foremost contributor in DNA methylation machinery, was revealed elevated in HCC and significantly correlates with poor prognosis. However, the transcriptional regulation of DNMT1 in HCC remains unknown. Real‐time PCR and immunohistochemistry were performed to detect DNMT1 and zinc finger transcription factor 191 (ZNF191) expressions in HCCs. Transcription activity of DNMT1promoter was analyzed with Luciferase reporter activity assay. The binding capacity of ZNF191 protein to DNMT1 promoter was examined with chromatin immunoprecipitation‐qPCR (ChIP‐qPCR) and electrophoretic mobility shift assay (EMSA). DNA methylation level of hepatoma cells was detected with Methylation array. ZNF191 can regulate DNMT1 mRNA and protein expression positively, and increase the transcription activity of the DNMT1 promoter. ChIP‐qPCR and EMSA revealed that ZNF191 protein directly binds to the DNMT1 promoter at nt‐240 AT(TCAT)3TC. Moreover, DNMT1 and ZNF191 expression correlate positively in human HCCs. With methylation array, DNA methylation alteration was observed in hepatoma cells with ZNF191 knockdown, and the differential methylation sites are enriched in the PI3K‐AKT pathway. Furthermore, we proved DNMT1 contributes the effect of ZNF191 on hepatoma cell growth via the PI3K‐AKT pathway. ZNF191 is a novel transcription regulator for DNMT1, and the pro‐proliferation effect of ZNF191/DNMT1/p‐AKT axis in hepatoma cells implies that ZNF191 status in HCCs may affect the therapeutic effect of DNMTs inhibitors and PI3K inhibitors for precise treatment of the disease. ZNF191 directly binds to DNMT1 promoter, and transactivates the DNMT1 gene. ZNF191 alters DNA methylation in hepatoma cells with DMS enriched in the PI3K‐AKT pathway. DNMT1 contributes the effect of ZNF191 on HCC cell growth via the PI3K‐AKT pathway.
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影响因子：
9.7
作者：
Pogribny, Igor P.;Rusyn, Ivan
通讯作者：
Rusyn, Ivan
Wnt8B受ZNF191转录调控，通过Wnt信号传导促进肝细胞癌细胞增殖
影响因子：
5.7
作者：
Liu Y;Wu D;Cheng H;Chen L;Zhang W;Zou L;Gao Q;Zhao Z;Chen Q;Zeng W;Zhang Z;Jiang W;Huang C;Liu G
通讯作者：
Liu G
影响因子：
11.2
作者：
Lin, Ruo-Kai;Wu, Chiu-Yi;Wang, Yi-Ching
通讯作者：
Wang, Yi-Ching
影响因子：
6
作者：
Qadir, Ximena V.;Han, Chang;Wu, Tong
通讯作者：
Wu, Tong
影响因子：
13.5
作者：
Nishida, Naoshi;Nagasaka, Takeshi;Goell, Ajay
通讯作者：
Goell, Ajay