GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage.

IF 2.7 4区医学 Q2 GENETICS & HEREDITY

Genes and Environment Pub Date : 2024-12-18 DOI:10.1186/s41021-024-00321-9

Xingxing Shao, Hailang Hou, Huijie Chen, Wan Xia, Xinpu Geng, Jindao Wang

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引用次数: 0

Abstract

Background: Lung adenocarcinoma (LUAD) is the most common histological type of non-small cell lung cancer (NSCLC). Platinum-based chemotherapy, such as cisplatin chemotherapy, is the cornerstone of treatment for LUAD patients. Nevertheless, cisplatin resistance remains the key obstacle to LUAD treatment, for its mechanism has not been fully elucidated.

Methods: HSD17B6 mRNA expression data were accessed from TCGA-LUAD database and differential expression analysis was performed. Enrichment analysis of HSD17B6 was conducted by GSEA, and its upstream transcription factors were predicted by hTFtarget. mRNA and protein expression levels of HSD17B6 and GATA1 were assayed by qRT-PCR and WB, and the binding relationship between them was verified by chromatin immunoprecipitation assay and dual luciferase reporter assay. Cell viability and IC₅₀ value of cisplatin-treated cells were measured by cell counting kit-8 assay. Cell cycle was assayed by flow cytometry. DNA damage level and DNA damage marker γ-H2AX expression were assayed by comet assay and western blot, respectively.

Results: HSD17B6 was lowly expressed in LUAD tissues and cells and mainly enriched in homologous recombination and mismatch repair pathways. As cell function experiments revealed, overexpression of HSD17B suppressed malignant phenotypes and cisplatin resistance in LUAD cells through DNA damage. Bioinformatics analysis revealed that GATA1 is the upstream regulator of HSD17B6, which was markedly reduced in LUAD tissues and cells. ChIP and dual luciferase reporter assays ascertained the binding of GATA1 to HSD17B6. Knockdown of GATA1 attenuated the effect of overexpression of HSD17B6 on LUAD cell behaviors and cisplatin resistance.

Conclusion: Transcription factor GATA1 could activate HSD17B6 to inhibit cisplatin resistance in LUAD through DNA damage, suggesting that GATA1/HSD17B6 axis may be a potential therapeutic target for chemotherapy resistance in LUAD patients.

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GATA1激活HSD17B6，通过DNA损伤提高顺铂治疗肺腺癌的疗效。

背景：肺腺癌（LUAD）是非小细胞肺癌（NSCLC）中最常见的组织学类型。以铂为基础的化疗，如顺铂化疗，是LUAD患者治疗的基石。然而，顺铂耐药仍然是LUAD治疗的主要障碍，其机制尚未完全阐明。方法：从TCGA-LUAD数据库获取HSD17B6 mRNA表达数据，进行差异表达分析。通过GSEA对HSD17B6进行富集分析，并通过hTFtarget预测其上游转录因子。采用qRT-PCR和WB检测HSD17B6和GATA1 mRNA和蛋白表达水平，采用染色质免疫沉淀法和双荧光素酶报告基因法验证两者的结合关系。采用细胞计数试剂盒-8法测定顺铂处理细胞的细胞活力和IC50值。流式细胞术检测细胞周期。分别用彗星法和western blot检测DNA损伤水平和DNA损伤标志物γ-H2AX的表达。结果：HSD17B6在LUAD组织和细胞中低表达，主要富集于同源重组和错配修复途径。细胞功能实验显示，过表达HSD17B通过DNA损伤抑制LUAD细胞的恶性表型和顺铂耐药性。生物信息学分析显示，GATA1是HSD17B6的上游调控因子，在LUAD组织和细胞中显著降低。ChIP和双荧光素酶报告基因检测确定了GATA1与HSD17B6的结合。敲低GATA1可减弱HSD17B6过表达对LUAD细胞行为和顺铂耐药的影响。结论：转录因子GATA1可通过DNA损伤激活HSD17B6抑制LUAD患者的顺铂耐药，提示GATA1/HSD17B6轴可能是LUAD患者化疗耐药的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Genes and Environment Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

4.00

自引率

0.00%

发文量

审稿时长

27 weeks

期刊介绍： Genes and Environment is an open access, peer-reviewed journal that aims to accelerate communications among global scientists working in the field of genes and environment. The journal publishes articles across a broad range of topics including environmental mutagenesis and carcinogenesis, environmental genomics and epigenetics, molecular epidemiology, genetic toxicology and regulatory sciences. Topics published in the journal include, but are not limited to, mutagenesis and anti-mutagenesis in bacteria; genotoxicity in mammalian somatic cells; genotoxicity in germ cells; replication and repair; DNA damage; metabolic activation and inactivation; water and air pollution; ROS, NO and photoactivation; pharmaceuticals and anticancer agents; radiation; endocrine disrupters; indirect mutagenesis; threshold; new techniques for environmental mutagenesis studies; DNA methylation (enzymatic); structure activity relationship; chemoprevention of cancer; regulatory science. Genetic toxicology including risk evaluation for human health, validation studies on testing methods and subjects of guidelines for regulation of chemicals are also within its scope.