睡眠剥夺对结肠癌的影响：揭示肿瘤脂质代谢和转移中的KynA-P4HA2-HIF-1α轴

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-02-06 DOI:10.1016/j.molmet.2025.102109

Zuojie Peng , Jia Song , Wenzhong Zhu , Haijun Bao , Yuan Hu , Yongping Shi , Xukai Cheng , Mi Jiang , Feifei Fang , Jinhuang Chen , Xiaogang Shu

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引用次数: 0

摘要

目的：越来越多的证据表明，睡眠不足会促进癌症的发展。此外，由于癌症疼痛和治疗副作用等因素，结肠癌患者经常经历睡眠剥夺。肝转移的发生是影响结肠癌患者死亡率的重要因素。然而，睡眠剥夺与结肠癌肝转移之间的关系尚未得到阐明。方法：建立睡眠剥夺肝转移模型，探讨睡眠剥夺对结肠癌肝转移的影响。随后，收集小鼠粪便进行非靶向代谢组学筛选和鉴定关键介质Kynurenic acid （KynA）。通过转录组学筛选HILPDA，并通过ChIP、co-IP、泛素化实验、表型实验等探索其潜在机制。结果：睡眠不足促进结肠癌肝转移。在功能上，睡眠剥夺会加重脂质积累，减少微生物代谢产物KynA的产生。相比之下，KynA在体外抑制结肠癌的进展。在体内，补充KynA逆转了睡眠剥夺对结肠癌肝转移的促进作用。机制上，KynA下调P4HA2的表达，促进HIF-1α的泛素化和降解，从而导致HILPDA的转录减少，最终导致结肠癌细胞脂解增加。结论：我们的研究结果表明，睡眠剥夺损害了KynA在细胞内的脂肪分解，导致结肠癌细胞中的脂滴积聚。这一过程最终促进了结肠癌肝转移。这为结肠癌的治疗提供了一个有希望的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis

查看原文本刊更多论文

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 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.

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.