GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage
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 LU...
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| Language: | English |
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BMC
2024-12-01
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| Series: | Genes and Environment |
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| Online Access: | https://doi.org/10.1186/s41021-024-00321-9 |
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| author | Xingxing Shao Hailang Hou Huijie Chen Wan Xia Xinpu Geng Jindao Wang |
| author_facet | Xingxing Shao Hailang Hou Huijie Chen Wan Xia Xinpu Geng Jindao Wang |
| author_sort | Xingxing Shao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e2deba1f09484dcb969d25e9ce22ee49 |
| institution | DOAJ |
| issn | 1880-7062 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Genes and Environment |
| spelling | doaj-art-e2deba1f09484dcb969d25e9ce22ee492025-08-20T02:40:18ZengBMCGenes and Environment1880-70622024-12-0146111110.1186/s41021-024-00321-9GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damageXingxing Shao0Hailang Hou1Huijie Chen2Wan Xia3Xinpu Geng4Jindao Wang5Pulmonary and Critical Care Medicine, Huaian Hospital of Huaian City, Huaian Cancer HospitalPulmonary and Critical Care Medicine, Huaian Hospital of Huaian City, Huaian Cancer HospitalPulmonary and Critical Care Medicine, Huaian Hospital of Huaian City, Huaian Cancer HospitalPulmonary and Critical Care Medicine, Huaian Hospital of Huaian City, Huaian Cancer HospitalPulmonary and Critical Care Medicine, Huaian Hospital of Huaian City, Huaian Cancer HospitalPulmonary and Critical Care Medicine, Huaian Hospital of Huaian City, Huaian Cancer HospitalAbstract 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.https://doi.org/10.1186/s41021-024-00321-9GATA1HSD17B6DNA damageLung adenocarcinomaCisplatin resistance |
| spellingShingle | Xingxing Shao Hailang Hou Huijie Chen Wan Xia Xinpu Geng Jindao Wang GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage Genes and Environment GATA1 HSD17B6 DNA damage Lung adenocarcinoma Cisplatin resistance |
| title | GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage |
| title_full | GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage |
| title_fullStr | GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage |
| title_full_unstemmed | GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage |
| title_short | GATA1 activates HSD17B6 to improve efficiency of cisplatin in lung adenocarcinoma via DNA damage |
| title_sort | gata1 activates hsd17b6 to improve efficiency of cisplatin in lung adenocarcinoma via dna damage |
| topic | GATA1 HSD17B6 DNA damage Lung adenocarcinoma Cisplatin resistance |
| url | https://doi.org/10.1186/s41021-024-00321-9 |
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