Abstract
BackgroundKrüppel-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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy and represents the third highest cause of cancer-related death worldwide, with an age-adjusted incidence of 10.1 new cases per 100,000 individualsWang et al Cancer Cell Int (2020) 20:422Krüppel-like factor 8 (KLF8) belongs to the KLF family of transcription factors, which shares the similar wellconserved zinc finger DNA-binding domains, and plays a critical role in controlling various cellular processes, such as cell cycle, proliferation, differentiation, and cell transformation [6,7,8]
We firstly investigated the functional role of KLF8 in hepatocellular carcinoma (HCC) tumorigenesis and explored the gene expression profile, as well as involved signaling pathways by using RNA sequencing (RNA-seq) combined with bioinformatics analyses[15, 16]
Knockout of KLF8 promoted cell apoptosis via up‐regulating the expression of apoptotic‐related genes To obtain the insight into the role of KLF8 on gene expression in HCC cells, we firstly established a stable KLF8 knockout HCC cell line LM3 (KLF8KO-LM3) using Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology
Summary
Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy and represents the third highest cause of cancer-related death worldwide, with an age-adjusted incidence of 10.1 new cases per 100,000 individualsWang et al Cancer Cell Int (2020) 20:422Krüppel-like factor 8 (KLF8) belongs to the KLF family of transcription factors, which shares the similar wellconserved zinc finger DNA-binding domains, and plays a critical role in controlling various cellular processes, such as cell cycle, proliferation, differentiation, and cell transformation [6,7,8]. Previous studies demonstrated that KLF8 was positively correlated with the metastatic potential of HCC and promoted HCC proliferation and invasion both in vitro and in vivo [10]. Our previous work confirmed the positive correlation between upregulation of KLF8 and poor prognosis of HCC patients, and identified the KLF8-mediated activation of Wnt/β-catenin signaling pathway as a novel regulatory mechanism underlying HCC tumorigenesis [12]. The detailed regulatory mechanisms of KLF8, as well as its potential roles in the promotion of HCC progression remain largely unknown. Krüppel-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. The functional role of KLF8 in the pathogenesis of hepatocellular carcinoma (HCC) remains largely unknown
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