A novel role of Kruppel-like factor 8 as an apoptosis repressor in hepatocellular carcinoma
A novel role of Kruppel-like factor 8 as an apoptosis repressor in hepatocellular carcinoma
复制标题
Krüppel 样因子 8 作为肝细胞癌凋亡抑制因子的新作用
DOI：
10.1186/s12935-020-01513-3
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发表时间：
2020-08-28
影响因子：
5.8
通讯作者：
Yang, Tian
中科院分区：
文献类型：
--
作者：
Wang, Ming-Da;Xing, Hao;Yang, Tian
kruppel样因子8 （KLF8）是一种调节关键基因转录和细胞癌症相关事件的促癌因子，与肿瘤的发生和进展有关。然而，KLF8在肝细胞癌（HCC）发病机制中的功能作用在很大程度上仍然未知。方法采用组蛋白H3赖氨酸27乙酰化（H3K27ac）的RNA测序（RNA-seq）和染色质免疫沉淀测序（ChIP-seq）结合生物信息学分析，分析KLF8基因敲除后肝癌细胞的基因表达模式和全基因组调控谱。通过基序分析评估KLF8识别的转录因子结合基序。对于预测的靶基因，通过ChIP检测转录变化，并通过siRNA转染进行功能丧失实验。结果sklf8在HCC中发挥转录抑制作用，主要直接调控凋亡相关基因。KLF8敲除后共鉴定出1816个差异表达基因，这些基因与H3K27ac状态的全球变化显著相关。此外，两个预测的靶基因，高迁移率组AT-hook 2 （HMGA2）和基质金属蛋白酶7 (MMP7)，被确定为HCC中klf8介导的抗凋亡作用的重要参与者。敲除KLF8可增强细胞凋亡过程并引起相关H3K27ac的增加，而抑制HMGA2或MMP7可减弱这些生物学效应。结论sour的研究提示了KLF8在肝癌中调控细胞凋亡的新作用和机制，有助于发现肝癌治疗的潜在靶点。
BackgroundKruppel-like factor 8 (KLF8), a cancer-promoting factor that regulates critical gene transcription and cellular cancer-related events, has been implicated in tumor development and progression. However, the functional role of KLF8 in the pathogenesis of hepatocellular carcinoma (HCC) remains largely unknown.MethodsThe gene expression patterns and genome-wide regulatory profiles of HCC cells after KLF8 knockout were analyzed by using RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) of histone H3 lysine 27 acetylation (H3K27ac) combined with bioinformatics analysis. Transcription factor-binding motifs that recognized by KLF8 were evaluated by motif analysis. For the predicted target genes, transcriptional changes were examined by ChIP, and loss of function experiments were conducted by siRNA transfection.ResultsKLF8 functioned as a transcription repressor in HCC and mainly regulated apoptotic-related genes directly. A total of 1,816 differentially expressed genes after KLF8 knockout were identified and significantly corresponded to global changes in H3K27ac status. Furthermore, two predicted target genes, high-mobility group AT-hook 2 (HMGA2) and matrix metalloproteinase 7 (MMP7), were identified as important participants in KLF8-mediated anti-apoptotic effect in HCC. Knockout of KLF8 enhanced cell apoptosis process and caused increase in the associated H3K27ac, whereas suppression HMGA2 or MMP7 attenuated these biological effects.ConclusionsOur work suggests a novel role and mechanism for KLF8 in the regulation of cell apoptosis in HCC and facilitates the discovery of potential therapeutic targets for HCC treatment.