DDX6 promotes invasion of hepatocellular carcinoma through CEBPB regulating fatty acid degradation

IF 0.9 Q4 GENETICS & HEREDITY

Gene Reports Pub Date : 2025-05-16 DOI:10.1016/j.genrep.2025.102259

Ziyu Wang , Mengyuan Cui , Linyue Zhao , Wen Jiang

{"title":"DDX6 promotes invasion of hepatocellular carcinoma through CEBPB regulating fatty acid degradation","authors":"Ziyu Wang , Mengyuan Cui , Linyue Zhao , Wen Jiang","doi":"10.1016/j.genrep.2025.102259","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Processing bodies (P-bodies), dynamic cytoplasmic ribonucleoprotein granules, play crucial roles in post-transcriptional regulation and translational control. However, their functional significance in hepatocellular carcinoma (HCC) pathogenesis remains poorly understood.</div></div><div><h3>Methods</h3><div>We systematically analyzed HCC datasets from public repositories using bioinformatics approaches. Cellular phenotypes were assessed through MTT proliferation assays and Transwell migration assays. Molecular mechanisms were investigated using enhanced crosslinking and immunoprecipitation sequencing (eCLIP-seq) for DDX6-RNA interactions and chromatin immunoprecipitation sequencing (ChIP-seq) for CEBPB transcriptional regulation.</div></div><div><h3>Results</h3><div>Clinical bioinformatics revealed that elevated DDX6 expression, a core component of P-body assembly, correlates with adverse prognosis in HCC patients. Functional studies demonstrated that DDX6 knockdown significantly attenuated HCC cell migration capacity. Integrated eCLIP-seq and transcriptomic profiling identified direct binding of DDX6 to CEBPB mRNA, leading to its destabilization and reduced expression. Gene set enrichment analysis (GSEA) uncovered a significant association between CEBPB levels and fatty acid degradation pathways. ChIP-seq validation confirmed that CEBPB binds to the promoter regions of fatty acid degradation (FAD) genes and regulates its expression. Functional validation confirmed that the suppression of CEBPB leads to impaired free fatty acid metabolism.</div></div><div><h3>Conclusions</h3><div>Our findings delineate a novel DDX6/CEBPB/FAD axis in HCC progression, where DDX6 post-transcriptionally suppresses CEBPB through mRNA binding, subsequently impairing FAD gene transcription. This mechanistic insight positions DDX6 as a promising therapeutic target for HCC intervention.</div></div>","PeriodicalId":12673,"journal":{"name":"Gene Reports","volume":"40 ","pages":"Article 102259"},"PeriodicalIF":0.9000,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gene Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2452014425001323","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Processing bodies (P-bodies), dynamic cytoplasmic ribonucleoprotein granules, play crucial roles in post-transcriptional regulation and translational control. However, their functional significance in hepatocellular carcinoma (HCC) pathogenesis remains poorly understood.

Methods

We systematically analyzed HCC datasets from public repositories using bioinformatics approaches. Cellular phenotypes were assessed through MTT proliferation assays and Transwell migration assays. Molecular mechanisms were investigated using enhanced crosslinking and immunoprecipitation sequencing (eCLIP-seq) for DDX6-RNA interactions and chromatin immunoprecipitation sequencing (ChIP-seq) for CEBPB transcriptional regulation.

Results

Clinical bioinformatics revealed that elevated DDX6 expression, a core component of P-body assembly, correlates with adverse prognosis in HCC patients. Functional studies demonstrated that DDX6 knockdown significantly attenuated HCC cell migration capacity. Integrated eCLIP-seq and transcriptomic profiling identified direct binding of DDX6 to CEBPB mRNA, leading to its destabilization and reduced expression. Gene set enrichment analysis (GSEA) uncovered a significant association between CEBPB levels and fatty acid degradation pathways. ChIP-seq validation confirmed that CEBPB binds to the promoter regions of fatty acid degradation (FAD) genes and regulates its expression. Functional validation confirmed that the suppression of CEBPB leads to impaired free fatty acid metabolism.

Conclusions

Our findings delineate a novel DDX6/CEBPB/FAD axis in HCC progression, where DDX6 post-transcriptionally suppresses CEBPB through mRNA binding, subsequently impairing FAD gene transcription. This mechanistic insight positions DDX6 as a promising therapeutic target for HCC intervention.

查看原文本刊更多论文

DDX6通过CEBPB调节脂肪酸降解促进肝癌侵袭

加工体（P-bodies）是动态的细胞质核糖核蛋白颗粒，在转录后调控和翻译控制中起着至关重要的作用。然而，它们在肝细胞癌（HCC）发病机制中的功能意义仍然知之甚少。方法采用生物信息学方法系统分析来自公共数据库的HCC数据集。通过MTT增殖试验和Transwell迁移试验评估细胞表型。使用增强交联和免疫沉淀测序（eCLIP-seq）研究DDX6-RNA相互作用的分子机制，使用染色质免疫沉淀测序（ChIP-seq）研究CEBPB转录调控。结果临床生物信息学显示，肝细胞癌患者p体组装核心成分DDX6表达升高与预后不良相关。功能研究表明，DDX6基因敲低可显著降低HCC细胞的迁移能力。综合eCLIP-seq和转录组学分析鉴定了DDX6与CEBPB mRNA的直接结合，导致其不稳定和表达降低。基因集富集分析（GSEA）揭示了CEBPB水平与脂肪酸降解途径之间的显著关联。ChIP-seq验证证实CEBPB与脂肪酸降解（FAD）基因的启动子区域结合并调节其表达。功能验证证实CEBPB的抑制导致游离脂肪酸代谢受损。我们的研究结果揭示了HCC发展过程中一个新的DDX6/CEBPB/FAD轴，其中DDX6通过mRNA结合抑制CEBPB转录后，进而损害FAD基因转录。这一机制使DDX6成为HCC干预的一个有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.