CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma
Abstract Tumor budding (TB) is a small tumor cell cluster with highly aggressive behavior located ahead of the invasive tumor front. However, the molecular and biological characteristics of TB and the regulatory mechanisms governing TB phenotypes remain unclear. This study reveals that TB exhibits a...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202305002 |
| _version_ | 1797262347952193536 |
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| author | Wenjin Wang Bokai Yun Rosalie G Hoyle Zhikun Ma Shadid Uz Zaman Gan Xiong Chen Yi Nan Xie Ming Zhang Xiqiang Liu Dipankar Bandyopadhyay Jiong Li Cheng Wang |
| author_facet | Wenjin Wang Bokai Yun Rosalie G Hoyle Zhikun Ma Shadid Uz Zaman Gan Xiong Chen Yi Nan Xie Ming Zhang Xiqiang Liu Dipankar Bandyopadhyay Jiong Li Cheng Wang |
| author_sort | Wenjin Wang |
| collection | DOAJ |
| description | Abstract Tumor budding (TB) is a small tumor cell cluster with highly aggressive behavior located ahead of the invasive tumor front. However, the molecular and biological characteristics of TB and the regulatory mechanisms governing TB phenotypes remain unclear. This study reveals that TB exhibits a particular dynamic gene signature with stemness and partial epithelial‐mesenchymal transition (p‐EMT). Importantly, nuclear expression of CYTOR is identified to be the key regulator governing stemness and the p‐EMT phenotype of TB cells, and targeting CYTOR significantly inhibits TB formation, tumor growth and lymph node metastasis in head and neck squamous cell carcinoma (HNSCC). Mechanistically, CYTOR promotes tumorigenicity and metastasis of TB cells by facilitating the formation of FOSL1 phase‐separated condensates to establish FOSL1‐dependent super enhancers (SEs). Depletion of CYTOR leads to the disruption of FOSL1‐dependent SEs, which results in the inactivation of cancer stemness and pro‐metastatic genes. In turn, activation of FOSL1 promotes the transcription of CYTOR. These findings indicate that CYTOR is a super‐lncRNA that controls the stemness and metastasis of TB cells through facilitating the formation of FOSL1 phase separation and SEs, which may be an attractive target for therapeutic interventions in HNSCC. |
| first_indexed | 2024-03-08T11:22:01Z |
| format | Article |
| id | doaj.art-f651aeea1f5547538cc62c069850f3d1 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-24T23:55:41Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-f651aeea1f5547538cc62c069850f3d12024-03-14T14:01:03ZengWileyAdvanced Science2198-38442024-01-01114n/an/a10.1002/advs.202305002CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell CarcinomaWenjin Wang0Bokai Yun1Rosalie G Hoyle2Zhikun Ma3Shadid Uz Zaman4Gan Xiong5Chen Yi6Nan Xie7Ming Zhang8Xiqiang Liu9Dipankar Bandyopadhyay10Jiong Li11Cheng Wang12Hospital of Stomatology Sun Yat‐sen University Guangzhou 510055 ChinaHospital of Stomatology Sun Yat‐sen University Guangzhou 510055 ChinaDepartment of Medicinal Chemistry School of Pharmacy Virginia Commonwealth University Richmond VA 23298‐0540 USADepartment of Medicinal Chemistry School of Pharmacy Virginia Commonwealth University Richmond VA 23298‐0540 USADepartment of Medicinal Chemistry School of Pharmacy Virginia Commonwealth University Richmond VA 23298‐0540 USAHospital of Stomatology Sun Yat‐sen University Guangzhou 510055 ChinaHospital of Stomatology Sun Yat‐sen University Guangzhou 510055 ChinaHospital of Stomatology Sun Yat‐sen University Guangzhou 510055 ChinaHospital of Stomatology Sun Yat‐sen University Guangzhou 510055 ChinaDepartment of Oral and Maxillofacial Surgery Nanfang Hospital, Southern Medical University Guangzhou 510515 ChinaDepartment of Biostatistics School of Medicine Virginia Commonwealth University Richmond VA 23298‐0540 USADepartment of Medicinal Chemistry School of Pharmacy Virginia Commonwealth University Richmond VA 23298‐0540 USAHospital of Stomatology Sun Yat‐sen University Guangzhou 510055 ChinaAbstract Tumor budding (TB) is a small tumor cell cluster with highly aggressive behavior located ahead of the invasive tumor front. However, the molecular and biological characteristics of TB and the regulatory mechanisms governing TB phenotypes remain unclear. This study reveals that TB exhibits a particular dynamic gene signature with stemness and partial epithelial‐mesenchymal transition (p‐EMT). Importantly, nuclear expression of CYTOR is identified to be the key regulator governing stemness and the p‐EMT phenotype of TB cells, and targeting CYTOR significantly inhibits TB formation, tumor growth and lymph node metastasis in head and neck squamous cell carcinoma (HNSCC). Mechanistically, CYTOR promotes tumorigenicity and metastasis of TB cells by facilitating the formation of FOSL1 phase‐separated condensates to establish FOSL1‐dependent super enhancers (SEs). Depletion of CYTOR leads to the disruption of FOSL1‐dependent SEs, which results in the inactivation of cancer stemness and pro‐metastatic genes. In turn, activation of FOSL1 promotes the transcription of CYTOR. These findings indicate that CYTOR is a super‐lncRNA that controls the stemness and metastasis of TB cells through facilitating the formation of FOSL1 phase separation and SEs, which may be an attractive target for therapeutic interventions in HNSCC.https://doi.org/10.1002/advs.202305002CYTORFOSL1head and neck squamous cell carcinomaphase separationsuper‐enhancer |
| spellingShingle | Wenjin Wang Bokai Yun Rosalie G Hoyle Zhikun Ma Shadid Uz Zaman Gan Xiong Chen Yi Nan Xie Ming Zhang Xiqiang Liu Dipankar Bandyopadhyay Jiong Li Cheng Wang CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma Advanced Science CYTOR FOSL1 head and neck squamous cell carcinoma phase separation super‐enhancer |
| title | CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma |
| title_full | CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma |
| title_fullStr | CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma |
| title_full_unstemmed | CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma |
| title_short | CYTOR Facilitates Formation of FOSL1 Phase Separation and Super Enhancers to Drive Metastasis of Tumor Budding Cells in Head and Neck Squamous Cell Carcinoma |
| title_sort | cytor facilitates formation of fosl1 phase separation and super enhancers to drive metastasis of tumor budding cells in head and neck squamous cell carcinoma |
| topic | CYTOR FOSL1 head and neck squamous cell carcinoma phase separation super‐enhancer |
| url | https://doi.org/10.1002/advs.202305002 |
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