大连医科大学Quentin Liu和Bai Cui研究组的一项最新研究报道，在睡眠不足增强的肿瘤发生中，致癌脂肪酸氧化感知昼夜节律中断。该项研究成果发表在2024年5月20日出版的《细胞—代谢》上。

昼夜节律紊乱预示着不良的癌症预后，然而昼夜节律紊乱如何在睡眠不足(SD)增强的肿瘤发生中被感知仍然不清楚。

在睡眠不足增强的肺肿瘤发生过程中，脂肪酸氧化(FAO)作为昼夜节律传感器，从时钟中断到致癌代谢信号的传递。无偏差转录组学和代谢组学分析均显示，脂肪酸氧化感知到睡眠不足诱导的昼夜节律中断，这是由长链脂肪酰基辅酶A合成酶1 (ACSL1)催化的棕榈酰辅酶A (PA-CoA)持续增加所导致的。

从机制上说，睡眠不足失调的CLOCK会过度激活ACSL1产生PA-CoA，从而以依赖ZDHHC5的方式促进CLOCK- Cys194 S-棕榈酰化。这种转录-棕榈酰化正反馈回路阻止了CLOCK的泛素-蛋白酶体降解，引导fao感知的昼夜节律中断，以维持sd增强的癌症干细胞。

有趣的是，定时β-内啡肽重置节律时钟和Acsl1的表达，以减轻睡眠不足增强的肿瘤发生。睡眠质量和血清β-内啡肽与癌症患者的癌症发展和CLOCK/ACSL1表达呈负相关，提示黎明补充β-内啡肽可能是睡眠不足相关癌症的一种潜在的时间治疗策略。

附：英文原文

Title: Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis

Author: 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, Guowang Xu, Ying Xu, Mindian Li, Keith W. Kelley, Bai Cui, Quentin Liu

Issue&Volume: 2024-05-20

Abstract: Circadian disruption predicts poor cancer prognosis, yet how circadian disruptionis sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, weshow fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruptionto oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomicand metabolomic analyses reveal that FAO senses SD-induced circadian disruption, asillustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chainfatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivatesACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependentmanner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomaldegradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhancedcancer stemness. Intriguingly, timed β-endorphin resets rhythmic Clock and Acsl1 expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum β-endorphinare negatively associated with both cancer development and CLOCK/ACSL1 expressionin patients with cancer, suggesting dawn-supplemented β-endorphin as a potential chronotherapeuticstrategy for SD-related cancer.

DOI: 10.1016/j.cmet.2024.04.018

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00138-4