Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis
Objective: There is growing evidence that sleep deprivation promotes cancer progression. In addition, colon cancer patients often experience sleep deprivation due to factors such as cancer pain and side effects of treatment. The occurrence of liver metastases is an important factor in the mortality...
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| Format: | Article |
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Elsevier
2025-03-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782500016X |
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| author | Zuojie Peng Jia Song Wenzhong Zhu Haijun Bao Yuan Hu Yongping Shi Xukai Cheng Mi Jiang Feifei Fang Jinhuang Chen Xiaogang Shu |
| author_facet | Zuojie Peng Jia Song Wenzhong Zhu Haijun Bao Yuan Hu Yongping Shi Xukai Cheng Mi Jiang Feifei Fang Jinhuang Chen Xiaogang Shu |
| author_sort | Zuojie Peng |
| collection | DOAJ |
| description | Objective: There is growing evidence that sleep deprivation promotes cancer progression. In addition, colon cancer patients often experience sleep deprivation due to factors such as cancer pain and side effects of treatment. The occurrence of liver metastases is an important factor in the mortality of colon cancer patients. However, the relationship between sleep deprivation and liver metastases from colon cancer has not been elucidated. Methods: A sleep deprivation liver metastasis model was constructed to evaluate the effect of sleep deprivation on liver metastasis of colon cancer. Subsequently, mice feces were collected for untargeted metabolomics to screen and identify the key mediator, Kynurenic acid (KynA). Furthermore, HILPDA was screened by transcriptomics, and its potential mechanism was explored through ChIP, co-IP, ubiquitination experiments, phenotyping experiments, etc. Results: Sleep deprivation promotes liver metastases in colon cancer. Functionally, sleep deprivation aggravates lipid accumulation and decreases the production of the microbiota metabolite KynA. In contrast, KynA inhibited colon cancer progression in vitro. In vivo, KynA supplementation reversed the promoting effects of sleep deprivation on liver metastases from colon cancer. Mechanistically, KynA downregulates the expression of P4HA2 to promote the ubiquitination and degradation of HIF-1α, which leads to a decrease in the transcription of HILPDA, and ultimately leads to an increase in lipolysis of colon cancer cells. Conclusions: Our findings reveal that sleep deprivation impairs intracellular lipolysis by KynA, leading to lipid droplets accumulation in colon cancer cells. This process ultimately promotes colon cancer liver metastasis. This suggests a promising strategy for colon cancer treatment. |
| format | Article |
| id | doaj-art-55f0477181ad4b5e8df84f4ff8e9dc8c |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-55f0477181ad4b5e8df84f4ff8e9dc8c2025-02-12T05:31:03ZengElsevierMolecular Metabolism2212-87782025-03-0193102109Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasisZuojie Peng0Jia Song1Wenzhong Zhu2Haijun Bao3Yuan Hu4Yongping Shi5Xukai Cheng6Mi Jiang7Feifei Fang8Jinhuang Chen9Xiaogang Shu10Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, ChinaDepartment of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, ChinaDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, ChinaDepartment of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, China; Corresponding author.Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No.1277, Wuhan 430022, Hubei, China; Corresponding author.Objective: There is growing evidence that sleep deprivation promotes cancer progression. In addition, colon cancer patients often experience sleep deprivation due to factors such as cancer pain and side effects of treatment. The occurrence of liver metastases is an important factor in the mortality of colon cancer patients. However, the relationship between sleep deprivation and liver metastases from colon cancer has not been elucidated. Methods: A sleep deprivation liver metastasis model was constructed to evaluate the effect of sleep deprivation on liver metastasis of colon cancer. Subsequently, mice feces were collected for untargeted metabolomics to screen and identify the key mediator, Kynurenic acid (KynA). Furthermore, HILPDA was screened by transcriptomics, and its potential mechanism was explored through ChIP, co-IP, ubiquitination experiments, phenotyping experiments, etc. Results: Sleep deprivation promotes liver metastases in colon cancer. Functionally, sleep deprivation aggravates lipid accumulation and decreases the production of the microbiota metabolite KynA. In contrast, KynA inhibited colon cancer progression in vitro. In vivo, KynA supplementation reversed the promoting effects of sleep deprivation on liver metastases from colon cancer. Mechanistically, KynA downregulates the expression of P4HA2 to promote the ubiquitination and degradation of HIF-1α, which leads to a decrease in the transcription of HILPDA, and ultimately leads to an increase in lipolysis of colon cancer cells. Conclusions: Our findings reveal that sleep deprivation impairs intracellular lipolysis by KynA, leading to lipid droplets accumulation in colon cancer cells. This process ultimately promotes colon cancer liver metastasis. This suggests a promising strategy for colon cancer treatment.http://www.sciencedirect.com/science/article/pii/S221287782500016XSleep deprivationColon cancerKynurenic acidLiver metastasisLipid metabolism |
| spellingShingle | Zuojie Peng Jia Song Wenzhong Zhu Haijun Bao Yuan Hu Yongping Shi Xukai Cheng Mi Jiang Feifei Fang Jinhuang Chen Xiaogang Shu Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis Molecular Metabolism Sleep deprivation Colon cancer Kynurenic acid Liver metastasis Lipid metabolism |
| title | Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis |
| title_full | Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis |
| title_fullStr | Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis |
| title_full_unstemmed | Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis |
| title_short | Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis |
| title_sort | impact of sleep deprivation on colon cancer unraveling the kyna p4ha2 hif 1α axis in tumor lipid metabolism and metastasis |
| topic | Sleep deprivation Colon cancer Kynurenic acid Liver metastasis Lipid metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S221287782500016X |
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