Targeting the FOXA1/BMI1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinoma
Abstract Nasopharyngeal carcinoma (NPC) is a highly aggressive head and neck cancer characterized by a complex etiology and a propensity for metastasis. The current study explores the intricate relationship between Forkhead Box A1 (FOXA1) and B-cell-specific Moloney murine leukemia virus integration...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02595-6 |
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| author | Yaping Qin Mingqing Yang Yunzhu Cao Yue Fu Fan Yang Xiaoling Zhang Shengjun Xiao |
| author_facet | Yaping Qin Mingqing Yang Yunzhu Cao Yue Fu Fan Yang Xiaoling Zhang Shengjun Xiao |
| author_sort | Yaping Qin |
| collection | DOAJ |
| description | Abstract Nasopharyngeal carcinoma (NPC) is a highly aggressive head and neck cancer characterized by a complex etiology and a propensity for metastasis. The current study explores the intricate relationship between Forkhead Box A1 (FOXA1) and B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) in the cancer progression and chemoresistance of NPC. Our research identified a significant downregulation of FOXA1 in NPC tissues and cell lines, which correlates with advanced clinical stages and poor differentiation, underscoring its potential role as a tumor suppressor. Functional assays demonstrated that the silencing of FOXA1 significantly enhanced the proliferation, migration, and invasive capabilities of NPC cells in vitro. Furthermore, the deficiency of FOXA1 was associated with a diminished sensitivity to cisplatin, as evidenced by increased cell viability, reduced apoptosis, and impaired cell cycle arrest upon drug exposure. Mechanistic studies revealed BMI1 as a critical downstream target of FOXA1. We observed a negative correlation between the expression levels of FOXA1 and BMI1 in NPC tissues. FOXA1 was shown to bind directly to the BMI1 promoter, effectively dampening its transcriptional activity. Rescue experiments indicated that the downregulation of BMI1 could partially reverse the malignant phenotypes induced by FOXA1 silencing, both in vitro and in vivo. Importantly, the knockdown of BMI1 significantly increased the chemosensitivity of FOXA1-depleted NPC cells to cisplatin, effectively counteracting the drug resistance associated with FOXA1 suppression. These findings highlight the pivotal role of FOXA1 in NPC development and progression and suggest that its loss leads to the upregulation of BMI1 and the acquisition of cisplatin resistance. Our study provides novel insights into the molecular mechanisms underlying the malignancy and chemoresistance of NPC and proposes that targeting the FOXA1/BMI1 axis could offer a promising therapeutic strategy for the treatment of this devastating disease. |
| format | Article |
| id | doaj-art-01bcdbc6db734e44b4b785e39dcdbc77 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-01bcdbc6db734e44b4b785e39dcdbc772025-08-20T04:01:47ZengNature Publishing GroupCell Death Discovery2058-77162025-07-0111111310.1038/s41420-025-02595-6Targeting the FOXA1/BMI1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinomaYaping Qin0Mingqing Yang1Yunzhu Cao2Yue Fu3Fan Yang4Xiaoling Zhang5Shengjun Xiao6Department of Pathology, The Second Affiliated Hospital of Guilin Medical UniversityDepartment of Clinical Laboratory Services, Liuzhou Workers’ HospitalDepartment of Pathology, The Second Affiliated Hospital of Guilin Medical UniversityDepartment of Pathology, The Second Affiliated Hospital of Guilin Medical UniversityDepartment of Pathology, The Affiliated Hospital of Guilin Medical UniversityDepartment of Physiology, Faculty of Basic Medical Sciences, Guilin Medical UniversityDepartment of Pathology, The Second Affiliated Hospital of Guilin Medical UniversityAbstract Nasopharyngeal carcinoma (NPC) is a highly aggressive head and neck cancer characterized by a complex etiology and a propensity for metastasis. The current study explores the intricate relationship between Forkhead Box A1 (FOXA1) and B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) in the cancer progression and chemoresistance of NPC. Our research identified a significant downregulation of FOXA1 in NPC tissues and cell lines, which correlates with advanced clinical stages and poor differentiation, underscoring its potential role as a tumor suppressor. Functional assays demonstrated that the silencing of FOXA1 significantly enhanced the proliferation, migration, and invasive capabilities of NPC cells in vitro. Furthermore, the deficiency of FOXA1 was associated with a diminished sensitivity to cisplatin, as evidenced by increased cell viability, reduced apoptosis, and impaired cell cycle arrest upon drug exposure. Mechanistic studies revealed BMI1 as a critical downstream target of FOXA1. We observed a negative correlation between the expression levels of FOXA1 and BMI1 in NPC tissues. FOXA1 was shown to bind directly to the BMI1 promoter, effectively dampening its transcriptional activity. Rescue experiments indicated that the downregulation of BMI1 could partially reverse the malignant phenotypes induced by FOXA1 silencing, both in vitro and in vivo. Importantly, the knockdown of BMI1 significantly increased the chemosensitivity of FOXA1-depleted NPC cells to cisplatin, effectively counteracting the drug resistance associated with FOXA1 suppression. These findings highlight the pivotal role of FOXA1 in NPC development and progression and suggest that its loss leads to the upregulation of BMI1 and the acquisition of cisplatin resistance. Our study provides novel insights into the molecular mechanisms underlying the malignancy and chemoresistance of NPC and proposes that targeting the FOXA1/BMI1 axis could offer a promising therapeutic strategy for the treatment of this devastating disease.https://doi.org/10.1038/s41420-025-02595-6 |
| spellingShingle | Yaping Qin Mingqing Yang Yunzhu Cao Yue Fu Fan Yang Xiaoling Zhang Shengjun Xiao Targeting the FOXA1/BMI1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinoma Cell Death Discovery |
| title | Targeting the FOXA1/BMI1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinoma |
| title_full | Targeting the FOXA1/BMI1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinoma |
| title_fullStr | Targeting the FOXA1/BMI1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinoma |
| title_full_unstemmed | Targeting the FOXA1/BMI1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinoma |
| title_short | Targeting the FOXA1/BMI1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinoma |
| title_sort | targeting the foxa1 bmi1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinoma |
| url | https://doi.org/10.1038/s41420-025-02595-6 |
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