FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancer
Gastric cancer is one of most lethal diseases across the world. However, the underlying mechanism of gastric cancer carcinogenesis and development is still not fully known. Forkhead box M1 (FOXM1) belongs to the FOX family and has crucial roles in transactivation of multiple oncogenes in several can...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558622000884 |
| _version_ | 1828057294663843840 |
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| author | Qingyun Tang Cheng Liu Shengwei Zhang Lijiao He Yunyi Liu Jing Wang Xiaoyan Zhao Xinzhe Li |
| author_facet | Qingyun Tang Cheng Liu Shengwei Zhang Lijiao He Yunyi Liu Jing Wang Xiaoyan Zhao Xinzhe Li |
| author_sort | Qingyun Tang |
| collection | DOAJ |
| description | Gastric cancer is one of most lethal diseases across the world. However, the underlying mechanism of gastric cancer carcinogenesis and development is still not fully known. Forkhead box M1 (FOXM1) belongs to the FOX family and has crucial roles in transactivation of multiple oncogenes in several cancer types, including gastric cancer. Recent studies have also shown the non-transcriptional function of FOXM1 via protein–protein interactions. Human telomerase reverse transcriptase (hTERT) is the core subunit of telomerase that facilitates cancer initiation and progression by maintaining cell immortalization, promoting cell proliferation and inhibiting cell apoptosis. However, the relationship between FOXM1 and hTERT in gastric cancer is still unclear. In our study, we found that FOXM1 and hTERT were convergent to the cell cycle-related pathways and they were positively related with advanced gastric cancer stages and poor outcomes. Simultaneous high levels of FOXM1 and hTERT predicted the worst prognosis. FOXM1 could increase hTERT protein rather than mRNA levels in a non-transcriptional manner. Mechanistically, FOXM1 interrupted the interaction between the E3 ligase MKRN1 and hTERT and decreased hTERT protein degradation. Further studies revealed that FOXM1 interacted with hTERT through its DNA-binding domain (DBD) region. Finally, we found that hTERT played important roles in FOXM1-mediated activation of the Wnt/β-catenin pathway to promote gastric cancer cell proliferation. Taken together, we found a novel non-classical function of FOXM1 to increase hTERT protein stability. Targeting the FOXM1-hTERT pathway may be a potential therapeutic strategy in treating gastric cancer. |
| first_indexed | 2024-04-10T21:10:22Z |
| format | Article |
| id | doaj.art-de315d5469a14b5394547b4679bf2a9c |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-04-10T21:10:22Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-de315d5469a14b5394547b4679bf2a9c2023-01-21T04:20:27ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862023-02-0136100863FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancerQingyun Tang0Cheng Liu1Shengwei Zhang2Lijiao He3Yunyi Liu4Jing Wang5Xiaoyan Zhao6Xinzhe Li7Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, ChinaDepartment of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, ChinaDepartment of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, ChinaDepartment of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, ChinaDepartment of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, ChinaDepartment of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, ChinaCorresponding authors.; Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, ChinaCorresponding authors.; Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, ChinaGastric cancer is one of most lethal diseases across the world. However, the underlying mechanism of gastric cancer carcinogenesis and development is still not fully known. Forkhead box M1 (FOXM1) belongs to the FOX family and has crucial roles in transactivation of multiple oncogenes in several cancer types, including gastric cancer. Recent studies have also shown the non-transcriptional function of FOXM1 via protein–protein interactions. Human telomerase reverse transcriptase (hTERT) is the core subunit of telomerase that facilitates cancer initiation and progression by maintaining cell immortalization, promoting cell proliferation and inhibiting cell apoptosis. However, the relationship between FOXM1 and hTERT in gastric cancer is still unclear. In our study, we found that FOXM1 and hTERT were convergent to the cell cycle-related pathways and they were positively related with advanced gastric cancer stages and poor outcomes. Simultaneous high levels of FOXM1 and hTERT predicted the worst prognosis. FOXM1 could increase hTERT protein rather than mRNA levels in a non-transcriptional manner. Mechanistically, FOXM1 interrupted the interaction between the E3 ligase MKRN1 and hTERT and decreased hTERT protein degradation. Further studies revealed that FOXM1 interacted with hTERT through its DNA-binding domain (DBD) region. Finally, we found that hTERT played important roles in FOXM1-mediated activation of the Wnt/β-catenin pathway to promote gastric cancer cell proliferation. Taken together, we found a novel non-classical function of FOXM1 to increase hTERT protein stability. Targeting the FOXM1-hTERT pathway may be a potential therapeutic strategy in treating gastric cancer.http://www.sciencedirect.com/science/article/pii/S1476558622000884Gastric cancerFOXM1hTERTubiquitinationWnt/β-catenin |
| spellingShingle | Qingyun Tang Cheng Liu Shengwei Zhang Lijiao He Yunyi Liu Jing Wang Xiaoyan Zhao Xinzhe Li FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancer Neoplasia: An International Journal for Oncology Research Gastric cancer FOXM1 hTERT ubiquitination Wnt/β-catenin |
| title | FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancer |
| title_full | FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancer |
| title_fullStr | FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancer |
| title_full_unstemmed | FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancer |
| title_short | FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancer |
| title_sort | foxm1 increases htert protein stability and indicates poor prognosis in gastric cancer |
| topic | Gastric cancer FOXM1 hTERT ubiquitination Wnt/β-catenin |
| url | http://www.sciencedirect.com/science/article/pii/S1476558622000884 |
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