TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma
Abstract Background Oral squamous cell carcinoma (OSCC), the predominant malignancy of the oral cavity, is characterized by high incidence and low survival rates. Emerging evidence suggests a link between circadian rhythm disruptions and cancer development. The circadian gene TIMELESS, known for its...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04791-3 |
| _version_ | 1797362925133889536 |
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| author | Yafan Chen Zhengyang Han Le Zhang Caihong Gao Jingyi Wei Xuyuan Yang Yabing Han Yunbo Li Chunmei Zhang Yixin Wei Jiaqi Dong Wenxing Xun Weifu Sun Taotao Zhang Hui Zhang Jingtao Chen Peng Yuan |
| author_facet | Yafan Chen Zhengyang Han Le Zhang Caihong Gao Jingyi Wei Xuyuan Yang Yabing Han Yunbo Li Chunmei Zhang Yixin Wei Jiaqi Dong Wenxing Xun Weifu Sun Taotao Zhang Hui Zhang Jingtao Chen Peng Yuan |
| author_sort | Yafan Chen |
| collection | DOAJ |
| description | Abstract Background Oral squamous cell carcinoma (OSCC), the predominant malignancy of the oral cavity, is characterized by high incidence and low survival rates. Emerging evidence suggests a link between circadian rhythm disruptions and cancer development. The circadian gene TIMELESS, known for its specific expression in various tumors, has not been extensively studied in the context of OSCC. This study aims to explore the influence of TIMELESS on OSCC, focusing on cell growth and metabolic alterations. Methods We analyzed TIMELESS expression in OSCC using western blot, immunohistochemistry, qRT-PCR, and data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). The role of TIMELESS in OSCC was examined through clone formation, MTS, cell cycle, and EdU assays, alongside subcutaneous tumor growth experiments in nude mice. We also assessed the metabolic impact of TIMELESS by measuring glucose uptake, lactate production, oxygen consumption, and medium pH, and investigated its effect on key metabolic proteins including silent information regulator 1 (SIRT1), hexokinase 2 (HK2), pyruvate kinase isozyme type M2 (PKM2), recombinant lactate dehydrogenase A (LDHA) and glucose transporter-1 (GLUT1). Results Elevated TIMELESS expression in OSCC tissues and cell lines was observed, correlating with reduced patient survival. TIMELESS overexpression enhanced OSCC cell proliferation, increased glycolytic activity (glucose uptake and lactate production), and suppressed oxidative phosphorylation (evidenced by reduced oxygen consumption and altered pH levels). Conversely, TIMELESS knockdown inhibited these cellular and metabolic processes, an effect mirrored by manipulating SIRT1 levels. Additionally, SIRT1 was positively associated with TIMELESS expression. The expression of SIRT1, HK2, PKM2, LDHA and GLUT1 increased with the overexpression of TIMELESS levels and decreased with the knockdown of TIMELESS. Conclusion TIMELESS exacerbates OSCC progression by modulating cellular proliferation and metabolic pathways, specifically by enhancing glycolysis and reducing oxidative phosphorylation, largely mediated through the SIRT1 pathway. This highlights TIMELESS as a potential target for OSCC therapeutic strategies. |
| first_indexed | 2024-03-08T16:14:26Z |
| format | Article |
| id | doaj.art-7bacd986f04e4e1cb3d76e4c6814ac4e |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-08T16:14:26Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-7bacd986f04e4e1cb3d76e4c6814ac4e2024-01-07T12:42:13ZengBMCJournal of Translational Medicine1479-58762024-01-0122111410.1186/s12967-023-04791-3TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinomaYafan Chen0Zhengyang Han1Le Zhang2Caihong Gao3Jingyi Wei4Xuyuan Yang5Yabing Han6Yunbo Li7Chunmei Zhang8Yixin Wei9Jiaqi Dong10Wenxing Xun11Weifu Sun12Taotao Zhang13Hui Zhang14Jingtao Chen15Peng Yuan16Department of Nuclear Medicine, Tangdu Hospital, Air Force Medical UniversityDepartment of Clinical Laboratory, Sinopharm Dongfeng General Hospital, Hubei University of MedicineDepartment of Interventional Radiology and Pain Treatment, Tangdu Hospital, Air Force Medical UniversityXi’an Physical Education UniversityThe First Clinical Medical College, Shaanxi University of Chinese MedicineSchool of Nursing and Rehabilitation, Xi’an Medical UniversityMedical College of Ankang UniversityDepartment of Nuclear Medicine, Tangdu Hospital, Air Force Medical UniversityDepartment of Nuclear Medicine, Tangdu Hospital, Air Force Medical UniversityDepartment of Nuclear Medicine, Tangdu Hospital, Air Force Medical UniversityThe Second Clinical Medical School, Shaanxi University of Chinese MedicineDepartment of Stomatology, Tangdu Hospital, Air Force Medical UniversityDepartment of Stomatology, Tangdu Hospital, Air Force Medical UniversityDepartment of Stomatology, Tangdu Hospital, Air Force Medical UniversityDepartment of Ultrasound Diagnosis, Xi’an Children’s HospitalDepartment of Stomatology, Tangdu Hospital, Air Force Medical UniversityDepartment of Nuclear Medicine, Tangdu Hospital, Air Force Medical UniversityAbstract Background Oral squamous cell carcinoma (OSCC), the predominant malignancy of the oral cavity, is characterized by high incidence and low survival rates. Emerging evidence suggests a link between circadian rhythm disruptions and cancer development. The circadian gene TIMELESS, known for its specific expression in various tumors, has not been extensively studied in the context of OSCC. This study aims to explore the influence of TIMELESS on OSCC, focusing on cell growth and metabolic alterations. Methods We analyzed TIMELESS expression in OSCC using western blot, immunohistochemistry, qRT-PCR, and data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). The role of TIMELESS in OSCC was examined through clone formation, MTS, cell cycle, and EdU assays, alongside subcutaneous tumor growth experiments in nude mice. We also assessed the metabolic impact of TIMELESS by measuring glucose uptake, lactate production, oxygen consumption, and medium pH, and investigated its effect on key metabolic proteins including silent information regulator 1 (SIRT1), hexokinase 2 (HK2), pyruvate kinase isozyme type M2 (PKM2), recombinant lactate dehydrogenase A (LDHA) and glucose transporter-1 (GLUT1). Results Elevated TIMELESS expression in OSCC tissues and cell lines was observed, correlating with reduced patient survival. TIMELESS overexpression enhanced OSCC cell proliferation, increased glycolytic activity (glucose uptake and lactate production), and suppressed oxidative phosphorylation (evidenced by reduced oxygen consumption and altered pH levels). Conversely, TIMELESS knockdown inhibited these cellular and metabolic processes, an effect mirrored by manipulating SIRT1 levels. Additionally, SIRT1 was positively associated with TIMELESS expression. The expression of SIRT1, HK2, PKM2, LDHA and GLUT1 increased with the overexpression of TIMELESS levels and decreased with the knockdown of TIMELESS. Conclusion TIMELESS exacerbates OSCC progression by modulating cellular proliferation and metabolic pathways, specifically by enhancing glycolysis and reducing oxidative phosphorylation, largely mediated through the SIRT1 pathway. This highlights TIMELESS as a potential target for OSCC therapeutic strategies.https://doi.org/10.1186/s12967-023-04791-3Oral squamous cell carcinoma (OSCC)TIMELESSGlucose metabolismSIRT1 |
| spellingShingle | Yafan Chen Zhengyang Han Le Zhang Caihong Gao Jingyi Wei Xuyuan Yang Yabing Han Yunbo Li Chunmei Zhang Yixin Wei Jiaqi Dong Wenxing Xun Weifu Sun Taotao Zhang Hui Zhang Jingtao Chen Peng Yuan TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma Journal of Translational Medicine Oral squamous cell carcinoma (OSCC) TIMELESS Glucose metabolism SIRT1 |
| title | TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma |
| title_full | TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma |
| title_fullStr | TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma |
| title_full_unstemmed | TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma |
| title_short | TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma |
| title_sort | timeless promotes reprogramming of glucose metabolism in oral squamous cell carcinoma |
| topic | Oral squamous cell carcinoma (OSCC) TIMELESS Glucose metabolism SIRT1 |
| url | https://doi.org/10.1186/s12967-023-04791-3 |
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