GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMT
Abstract Cisplatin (CDDP) based chemotherapy has emerged as the predominant therapeutic regimen for patients with advanced gastric cancer (GC). However, its efficacy is dampened by the development of chemoresistance, which results in poor prognosis of patients. GLI2, a key transcription factor in th...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-03-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07564-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850065618596790272 |
|---|---|
| author | Wenshuai Zhu Jingguo Sun Fubo Jing Yuanxin Xing Muhua Luan Zhaotian Feng Xiaoli Ma Yunshan Wang Yanfei Jia |
| author_facet | Wenshuai Zhu Jingguo Sun Fubo Jing Yuanxin Xing Muhua Luan Zhaotian Feng Xiaoli Ma Yunshan Wang Yanfei Jia |
| author_sort | Wenshuai Zhu |
| collection | DOAJ |
| description | Abstract Cisplatin (CDDP) based chemotherapy has emerged as the predominant therapeutic regimen for patients with advanced gastric cancer (GC). However, its efficacy is dampened by the development of chemoresistance, which results in poor prognosis of patients. GLI2, a key transcription factor in the Hedgehog (Hh) signaling pathway, is regarded as a target for cancer therapy. However, the significance of GLI2 for CDDP resistance in GC has not been well established. Here, we show that GLI2 expression was upregulated in EMT-type GC and associated with poor prognosis. GLI2 promotes proliferation, migration, and CDDP resistance of GC cells by inducing EMT. In terms of mechanism, GLI2 binds to the promoter region of DEC1 and enhances its expression, thereby co-transcriptionally regulating ZEB1 expression. Animal experiments have demonstrated that both GLI2 knockdown and GLI2 inhibitor significantly enhance CDDP sensitivity in GC. Our data not only identify a novel GLI2/DEC1/ZEB1/EMT pathway in GC CDDP resistance but also provide novel strategies to treat GC in the future. |
| format | Article |
| id | doaj-art-9b3260992e6746c29887a780fa784ba2 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-9b3260992e6746c29887a780fa784ba22025-08-20T02:48:57ZengNature Publishing GroupCell Death and Disease2041-48892025-03-0116111510.1038/s41419-025-07564-6GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMTWenshuai Zhu0Jingguo Sun1Fubo Jing2Yuanxin Xing3Muhua Luan4Zhaotian Feng5Xiaoli Ma6Yunshan Wang7Yanfei Jia8Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical UniversityResearch Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical UniversityResearch Center of Basic Medicine, Jinan Central Hospital, Shandong UniversityResearch Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical UniversityResearch Center of Basic Medicine, Jinan Central Hospital, Shandong UniversityDepartment of Medical Laboratory, Shandong Second Medical UniversityResearch Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical UniversityResearch Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical UniversityResearch Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical UniversityAbstract Cisplatin (CDDP) based chemotherapy has emerged as the predominant therapeutic regimen for patients with advanced gastric cancer (GC). However, its efficacy is dampened by the development of chemoresistance, which results in poor prognosis of patients. GLI2, a key transcription factor in the Hedgehog (Hh) signaling pathway, is regarded as a target for cancer therapy. However, the significance of GLI2 for CDDP resistance in GC has not been well established. Here, we show that GLI2 expression was upregulated in EMT-type GC and associated with poor prognosis. GLI2 promotes proliferation, migration, and CDDP resistance of GC cells by inducing EMT. In terms of mechanism, GLI2 binds to the promoter region of DEC1 and enhances its expression, thereby co-transcriptionally regulating ZEB1 expression. Animal experiments have demonstrated that both GLI2 knockdown and GLI2 inhibitor significantly enhance CDDP sensitivity in GC. Our data not only identify a novel GLI2/DEC1/ZEB1/EMT pathway in GC CDDP resistance but also provide novel strategies to treat GC in the future.https://doi.org/10.1038/s41419-025-07564-6 |
| spellingShingle | Wenshuai Zhu Jingguo Sun Fubo Jing Yuanxin Xing Muhua Luan Zhaotian Feng Xiaoli Ma Yunshan Wang Yanfei Jia GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMT Cell Death and Disease |
| title | GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMT |
| title_full | GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMT |
| title_fullStr | GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMT |
| title_full_unstemmed | GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMT |
| title_short | GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMT |
| title_sort | gli2 inhibits cisplatin sensitivity in gastric cancer through dec1 zeb1 mediated emt |
| url | https://doi.org/10.1038/s41419-025-07564-6 |
| work_keys_str_mv | AT wenshuaizhu gli2inhibitscisplatinsensitivityingastriccancerthroughdec1zeb1mediatedemt AT jingguosun gli2inhibitscisplatinsensitivityingastriccancerthroughdec1zeb1mediatedemt AT fubojing gli2inhibitscisplatinsensitivityingastriccancerthroughdec1zeb1mediatedemt AT yuanxinxing gli2inhibitscisplatinsensitivityingastriccancerthroughdec1zeb1mediatedemt AT muhualuan gli2inhibitscisplatinsensitivityingastriccancerthroughdec1zeb1mediatedemt AT zhaotianfeng gli2inhibitscisplatinsensitivityingastriccancerthroughdec1zeb1mediatedemt AT xiaolima gli2inhibitscisplatinsensitivityingastriccancerthroughdec1zeb1mediatedemt AT yunshanwang gli2inhibitscisplatinsensitivityingastriccancerthroughdec1zeb1mediatedemt AT yanfeijia gli2inhibitscisplatinsensitivityingastriccancerthroughdec1zeb1mediatedemt |