Silencing of KIAA1429, a N6-methyladenine methyltransferase, inhibits the progression of colon adenocarcinoma via blocking the hypoxia-inducible factor 1 signalling pathway
Canhui Ouyang, Guofeng Xu, Jun Xie, Yun Xie, Yun Zhou
{"title":"Silencing of KIAA1429, a N6-methyladenine methyltransferase, inhibits the progression of colon adenocarcinoma via blocking the hypoxia-inducible factor 1 signalling pathway","authors":"Canhui Ouyang, Guofeng Xu, Jun Xie, Yun Xie, Yun Zhou","doi":"10.1002/jbt.23829","DOIUrl":null,"url":null,"abstract":"<p><i>KIAA1429</i> is an important ‘writer’ of the N6-methyladenine (m<sup>6</sup>A) modification, which is involved in tumour progression. This study was conducted to explore the mechanism of action of <i>KIAA1429</i> in colon adenocarcinoma (COAD). <i>KIAA1429</i>-silenced COAD cell and xenograft tumour models were constructed, and the function of <i>KIAA1429</i> was explored through a series of in vivo and in vitro assays. The downstream mechanisms of <i>KIAA1429</i> were explored using transcriptome sequencing. Dimethyloxalylglycine (DMOG), an activator of <i>HIF-1α</i>, was used for feedback verification. The expression of <i>KIAA1429</i> in COAD tumour tissues and cells was elevated, and <i>KIAA1429</i> exhibited differential expression at different stages of the tumour. Silencing of <i>KIAA1429</i> inhibited the proliferation, migration, and invasion of HT29 and HCT116 cells. The expression levels of <i>NLRP3</i>, <i>GSDMD</i> and <i>Caspase-1</i> were decreased in <i>KIAA1429</i>-silenced HT29 cells, indicating the pyroptotic activity was inhibited. Additionally, <i>KIAA1429</i> silencing inhibited the growth of tumour xenograft. Transcriptome sequencing and reverse transcription quantitative polymerase chain reaction revealed that after <i>KIAA1429</i> silencing, the expression of <i>AKR1C1</i>, <i>AKR1C2</i>, <i>AKR1C3</i> and <i>RDH8</i> was elevated, and the expression of <i>VIRMA</i>, <i>GINS1</i>, <i>VBP1</i> and <i>ARF3</i> was decreased. In HT29 cells, <i>KIAA1429</i> silencing blocked the <i>HIF-1</i> signalling pathway, accompanied by the decrease in <i>AKT1</i> and <i>HIF-1α</i> protein levels. The activation of <i>HIF-1</i> signalling pathway, mediated by DMOG, reversed the antitumour role of <i>KIAA1429</i> silencing. <i>KIAA1429</i> silencing inhibits COAD development by blocking the <i>HIF-1</i> signalling pathway.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"38 9","pages":""},"PeriodicalIF":3.2000,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biochemical and Molecular Toxicology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jbt.23829","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
KIAA1429 is an important ‘writer’ of the N6-methyladenine (m6A) modification, which is involved in tumour progression. This study was conducted to explore the mechanism of action of KIAA1429 in colon adenocarcinoma (COAD). KIAA1429-silenced COAD cell and xenograft tumour models were constructed, and the function of KIAA1429 was explored through a series of in vivo and in vitro assays. The downstream mechanisms of KIAA1429 were explored using transcriptome sequencing. Dimethyloxalylglycine (DMOG), an activator of HIF-1α, was used for feedback verification. The expression of KIAA1429 in COAD tumour tissues and cells was elevated, and KIAA1429 exhibited differential expression at different stages of the tumour. Silencing of KIAA1429 inhibited the proliferation, migration, and invasion of HT29 and HCT116 cells. The expression levels of NLRP3, GSDMD and Caspase-1 were decreased in KIAA1429-silenced HT29 cells, indicating the pyroptotic activity was inhibited. Additionally, KIAA1429 silencing inhibited the growth of tumour xenograft. Transcriptome sequencing and reverse transcription quantitative polymerase chain reaction revealed that after KIAA1429 silencing, the expression of AKR1C1, AKR1C2, AKR1C3 and RDH8 was elevated, and the expression of VIRMA, GINS1, VBP1 and ARF3 was decreased. In HT29 cells, KIAA1429 silencing blocked the HIF-1 signalling pathway, accompanied by the decrease in AKT1 and HIF-1α protein levels. The activation of HIF-1 signalling pathway, mediated by DMOG, reversed the antitumour role of KIAA1429 silencing. KIAA1429 silencing inhibits COAD development by blocking the HIF-1 signalling pathway.
期刊介绍:
The Journal of Biochemical and Molecular Toxicology is an international journal that contains original research papers, rapid communications, mini-reviews, and book reviews, all focusing on the molecular mechanisms of action and detoxication of exogenous and endogenous chemicals and toxic agents. The scope includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, lactivation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology.