Fei Peng, Jinxin Lu, Keyu Su, Xinyu Liu, Huandong Luo, Bin He, Cenxin Wang, Xiaoyu Zhang, Fan An, Dekang Lv, Yuanyuan Luo, Qitong Su, Tonghui Jiang, Ziqian Deng, Bin He, Lingzhi Xu, Tao Guo, Jin Xiang, Chundong Gu, Ling Wang, Quentin Liu
{"title":"致癌脂肪酸氧化在睡眠不足导致的肿瘤发生过程中感知昼夜节律紊乱","authors":"Fei Peng, Jinxin Lu, Keyu Su, Xinyu Liu, Huandong Luo, Bin He, Cenxin Wang, Xiaoyu Zhang, Fan An, Dekang Lv, Yuanyuan Luo, Qitong Su, Tonghui Jiang, Ziqian Deng, Bin He, Lingzhi Xu, Tao Guo, Jin Xiang, Chundong Gu, Ling Wang, Quentin Liu","doi":"10.1016/j.cmet.2024.04.018","DOIUrl":null,"url":null,"abstract":"<p>Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed β-endorphin resets rhythmic <em>Clock</em> and <em>Acsl1</em> expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum β-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented β-endorphin as a potential chronotherapeutic strategy for SD-related cancer.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":null,"pages":null},"PeriodicalIF":27.7000,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis\",\"authors\":\"Fei Peng, Jinxin Lu, Keyu Su, Xinyu Liu, Huandong Luo, Bin He, Cenxin Wang, Xiaoyu Zhang, Fan An, Dekang Lv, Yuanyuan Luo, Qitong Su, Tonghui Jiang, Ziqian Deng, Bin He, Lingzhi Xu, Tao Guo, Jin Xiang, Chundong Gu, Ling Wang, Quentin Liu\",\"doi\":\"10.1016/j.cmet.2024.04.018\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed β-endorphin resets rhythmic <em>Clock</em> and <em>Acsl1</em> expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum β-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented β-endorphin as a potential chronotherapeutic strategy for SD-related cancer.</p>\",\"PeriodicalId\":9840,\"journal\":{\"name\":\"Cell metabolism\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2024-05-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell metabolism\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cmet.2024.04.018\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell metabolism","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.cmet.2024.04.018","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis
Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed β-endorphin resets rhythmic Clock and Acsl1 expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum β-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented β-endorphin as a potential chronotherapeutic strategy for SD-related cancer.
期刊介绍:
Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others.
Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.