Fatty Acid Oxidation in Lung Cancer Patients Induced by Sleep Loss Promotes Tumorigenesis Through Circadian Rhythm Disruption

Background and Research Motivation

Circadian rhythm regulation is one of the critical mechanisms for animals to maintain physiological homeostasis. However, disruptions in circadian rhythms have become a common phenomenon due to modern lifestyles. Such disruptions not only cause immune dysfunction and metabolic disorders but may also lead to cancer recurrence and tumor immune evasion. Previous studies have shown that sleep deficiency (SD) promotes cancer metastasis, tumor growth, and cancer immune evasion. However, the mechanism by which circadian rhythm disruption is sensed through metabolic reprogramming to promote sleep deficiency-related cancer development remains unclear.

Paper Source and Research Team

This study was authored by researchers Peng Fei, Jinxin Lu, Keyu Su, and others from various research institutions, including the Cancer Stem Cell Institute of Dalian Medical University, the State Key Laboratory of Oncology in South China, and the National Chromatography Research and Application Center. The paper was published on July 2, 2024, in the journal Cell Metabolism, with Bai Cui and Quentin Liu serving as corresponding authors.

Research Methods and Procedures

In this study, the authors conducted a series of experiments to reveal how fatty acid oxidation (FAO), as a circadian rhythm sensing mechanism, enhances tumorigenesis through sleep deficiency. Their research process is as follows:

1. Experimental Subjects and Treatment: Wild-type C57BL/6J mice were subjected to sleep deficiency and lung tissue samples were collected at Zeitgeber times (ZT) 0, 4, 8, 12, 16, 20, and 24 (corresponding to 8 AM, 4 PM, 8 PM, midnight, etc.). Electrophysiological techniques confirmed that the wakefulness time of treated mice increased compared to the control group, while non-rapid eye movement (NREM) and rapid eye movement (REM) sleep times decreased.

2. Transcriptomic and Metabolomic Analyses: Using RNA sequencing and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS), transcriptomic and metabolomic analyses were performed on lung tissue samples from control and sleep-deficient mice. The results showed that sleep deficiency significantly disrupted the circadian rhythm expression of approximately 3,284 genes, with the circadian rhythm of genes related to fatty acid oxidation also being significantly affected.

3. Tumor Model Construction and Evaluation: Using the K-rASLSL-G12D mouse model to induce lung cancer, mice were divided into control and sleep-deficient groups. The results indicated that sleep deficiency accelerated tumor initiation and progression. Furthermore, a patient-derived xenograft (PDX) model in mice showed that sleep deficiency significantly increased tumor volume and elevated the expression of stemness markers.

4. Functional Validation Experiments: Sleep-deficient mice were treated with the fatty acid oxidation inhibitor etomoxir. The results demonstrated that such treatment could reverse the enhanced tumorigenesis induced by sleep deficiency. Additionally, the levels of oxidative metabolites such as acetyl-CoA and ATP in vivo also decreased.

Major Research Findings

1. Fatty Acid Oxidation Sensing of Sleep Deficiency Impacts Circadian Rhythms: The experimental results showed that prolonged sleep deficiency led to a significant upregulation of acyl-CoA synthetase long-chain family member 1 (ACSL1), which, through S-palmitoylation, regulates the stability of the circadian rhythm clock gene (Clock) protein. This established a positive feedback loop, promoting enhanced tumor stemness.

2. Time-Dependent β-Endorphin Treatment: In response to the circadian rhythm disorder of Clock and ACSL1 gene expression, the research team employed β-endorphin treatment at different time points and continuous administration. It was found that daily β-endorphin treatment at ZT8 (4 PM) could optimally restore circadian rhythms and significantly reduce tumorigenesis induced by sleep deficiency.

3. Clinical Relevance and Prognostic Prediction: Prospective and retrospective studies revealed that sleep quality and serum β-endorphin levels were negatively correlated with Clock and ACSL1 expression in lung cancer patients. Poor sleep quality and low β-endorphin levels predicted poor cancer prognosis, while high Clock and ACSL1 expression were associated with severe tumor characteristics.

Research Conclusions and Significance

This study reveals that fatty acid oxidation acts as a sensing mechanism for circadian rhythm disruption, regulating the circadian rhythm gene Clock through S-palmitoylation, thereby maintaining tumor stemness under sleep deficiency. The research also proposes a time-dependent β-endorphin supplementation strategy to reset circadian rhythms, providing a potential anti-tumor treatment strategy. Clinical data further support that β-endorphin, Clock, and ACSL1 can serve as prognostic indicators for lung cancer.

Research Highlights

1. Innovative Approach: This study is the first to validate the mechanism by which ACSL1 maintains tumor stemness through the S-palmitoylation of the circadian rhythm gene Clock.
2. Clinical Significance: The study proposes the time-dependent supplementation of β-endorphin to mitigate tumorigenesis caused by sleep deficiency, offering a new perspective for cancer treatment.
3. Broad Application Prospects: This research provides a theoretical foundation for studying the influence of circadian rhythms on cancer development. Clinically, it may be possible to inhibit tumor progression by improving sleep quality and regulating endocrine functions.

The results of this study not only uncover the mechanisms by which sleep deficiency and circadian rhythm disruption promote tumorigenesis but also provide new intervention methods for clinical practice, improving the management of cancer patient prognosis.