Donafenib and GSK‐J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 Expression
Abstract Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Donafenib is a multi‐receptor tyrosine kinase inhibitor approved for the treatment of patients with advanced HCC, but its clinical effect is very limited. Here, through integrated screening of a small‐molecule inhib...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-08-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202206798 |
| _version_ | 1797754725145247744 |
|---|---|
| author | Chenyang Zheng Bo Zhang Yunyun Li Kejia Liu Wei Wei Shuhang Liang Hongrui Guo Kun Ma Yao Liu Jiabei Wang Lianxin Liu |
| author_facet | Chenyang Zheng Bo Zhang Yunyun Li Kejia Liu Wei Wei Shuhang Liang Hongrui Guo Kun Ma Yao Liu Jiabei Wang Lianxin Liu |
| author_sort | Chenyang Zheng |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Donafenib is a multi‐receptor tyrosine kinase inhibitor approved for the treatment of patients with advanced HCC, but its clinical effect is very limited. Here, through integrated screening of a small‐molecule inhibitor library and a druggable CRISPR library, that GSK‐J4 is synthetically lethal with donafenib in liver cancer is shown. This synergistic lethality is validated in multiple HCC models, including xenograft, orthotopically induced HCC, patient‐derived xenograft, and organoid models. Furthermore, co‐treatment with donafenib and GSK‐J4 resulted in cell death mainly via ferroptosis. Mechanistically, through integrated RNA sequencing (RNA‐seq) and assay for transposase‐accessible chromatin with high throughput sequencing (ATAC‐seq) analyses, that donafenib and GSK‐J4 synergistically promoted the expression of HMOX1 and increased the intracellular Fe2+ level is found, eventually leading to ferroptosis. Additionally, through cleavage under targets & tagmentation followed by sequencing (CUT&Tag‐seq), it is found that the enhancer regions upstream of HMOX1 promoter significantly increased under donafenib and GSK‐J4 co‐treatment. A chromosome conformation capture assay confirmed that the increased expression of HMOX1 is caused by the significantly enhanced interaction between the promoter and upstream enhancer under dual‐drug combination. Taken together, this study elucidates a new synergistic lethal interaction in liver cancer. |
| first_indexed | 2024-03-12T17:37:44Z |
| format | Article |
| id | doaj.art-767893fd29cb417b8fd4d58925a32ba2 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-12T17:37:44Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-767893fd29cb417b8fd4d58925a32ba22023-08-04T07:49:49ZengWileyAdvanced Science2198-38442023-08-011022n/an/a10.1002/advs.202206798Donafenib and GSK‐J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 ExpressionChenyang Zheng0Bo Zhang1Yunyun Li2Kejia Liu3Wei Wei4Shuhang Liang5Hongrui Guo6Kun Ma7Yao Liu8Jiabei Wang9Lianxin Liu10Department of Hepatobiliary Surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 ChinaAnhui Province Key Laboratory of Hepatopancreatobiliary Surgery Hefei Anhui 230001 ChinaDepartment of Hepatobiliary Surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 ChinaHefei National Laboratory for Physical Sciences at the Microscale Division of Life Sciences and Medicine CAS Centre for Excellence in Molecular Cell Science University of Science and Technology of China Hefei Anhui 230001 ChinaDepartment of Hepatobiliary Surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 ChinaAnhui Province Key Laboratory of Hepatopancreatobiliary Surgery Hefei Anhui 230001 ChinaDepartment of Hepatobiliary Surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 ChinaDepartment of Hepatic Surgery Key Laboratory of Hepatosplenic Surgery Ministry of Education The First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang 150007 ChinaDepartment of Hepatobiliary Surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 ChinaDepartment of Hepatobiliary Surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 ChinaDepartment of Hepatobiliary Surgery The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 ChinaAbstract Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Donafenib is a multi‐receptor tyrosine kinase inhibitor approved for the treatment of patients with advanced HCC, but its clinical effect is very limited. Here, through integrated screening of a small‐molecule inhibitor library and a druggable CRISPR library, that GSK‐J4 is synthetically lethal with donafenib in liver cancer is shown. This synergistic lethality is validated in multiple HCC models, including xenograft, orthotopically induced HCC, patient‐derived xenograft, and organoid models. Furthermore, co‐treatment with donafenib and GSK‐J4 resulted in cell death mainly via ferroptosis. Mechanistically, through integrated RNA sequencing (RNA‐seq) and assay for transposase‐accessible chromatin with high throughput sequencing (ATAC‐seq) analyses, that donafenib and GSK‐J4 synergistically promoted the expression of HMOX1 and increased the intracellular Fe2+ level is found, eventually leading to ferroptosis. Additionally, through cleavage under targets & tagmentation followed by sequencing (CUT&Tag‐seq), it is found that the enhancer regions upstream of HMOX1 promoter significantly increased under donafenib and GSK‐J4 co‐treatment. A chromosome conformation capture assay confirmed that the increased expression of HMOX1 is caused by the significantly enhanced interaction between the promoter and upstream enhancer under dual‐drug combination. Taken together, this study elucidates a new synergistic lethal interaction in liver cancer.https://doi.org/10.1002/advs.202206798donafenibferroptosisgsk‐j4hmox1synthetic lethal |
| spellingShingle | Chenyang Zheng Bo Zhang Yunyun Li Kejia Liu Wei Wei Shuhang Liang Hongrui Guo Kun Ma Yao Liu Jiabei Wang Lianxin Liu Donafenib and GSK‐J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 Expression Advanced Science donafenib ferroptosis gsk‐j4 hmox1 synthetic lethal |
| title | Donafenib and GSK‐J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 Expression |
| title_full | Donafenib and GSK‐J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 Expression |
| title_fullStr | Donafenib and GSK‐J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 Expression |
| title_full_unstemmed | Donafenib and GSK‐J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 Expression |
| title_short | Donafenib and GSK‐J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 Expression |
| title_sort | donafenib and gsk j4 synergistically induce ferroptosis in liver cancer by upregulating hmox1 expression |
| topic | donafenib ferroptosis gsk‐j4 hmox1 synthetic lethal |
| url | https://doi.org/10.1002/advs.202206798 |
| work_keys_str_mv | AT chenyangzheng donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT bozhang donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT yunyunli donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT kejialiu donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT weiwei donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT shuhangliang donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT hongruiguo donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT kunma donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT yaoliu donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT jiabeiwang donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression AT lianxinliu donafenibandgskj4synergisticallyinduceferroptosisinlivercancerbyupregulatinghmox1expression |