The mammalian circadian machinery consists of an autoregulatory transcription-translation feedback loop. NSCLC is a cancer of epithelial origin ( 13, 14), so this reinforces the hypothesis that disruption of the circadian machinery could trigger harmful events due to dysregulation of homeostasis, resulting in increased risk of lung tumor development. Selective ablation of bronchiolar epithelial cells results in the loss of circadian clock oscillations in mouse lung slices, demonstrating that airway epithelial cells are key circadian oscillators within the lung ( 12). The lung is under tight circadian control, as evidenced by robust 24-hour rhythms in intrinsic defense mechanisms and lung physiology indices such as lung resistance and peak expiratory flow ( 11). Despite extensive characterization of genetic events that contribute to lung cancer, there has been relatively little research addressing the impact of environmental circadian disruption on lung tumorigenesis in humans. The LUAD subtype of non–small cell lung cancer (NSCLC) is the most prevalent form of lung cancer, and Kirsten rat sarcoma (KRAS) is the most frequently mutated oncogene in human LUAD ( 10). Lung cancer is the leading cause of cancer deaths in men and women worldwide ( 8, 9). Several human and animal studies have demonstrated that disruption of circadian rhythms, either by genetic or environmental means, enhances cancer risk ( 2), including the risk of lung adenocarcinoma (LUAD) ( 3– 7). industries work irregular schedules, including night and rotating shifts ( 1). In 2015, the National Health Interview Survey revealed that 12 to 35% of the workforce in various U.S. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological or genetic inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. We demonstrate that exposure to chronic circadian disruption increases tumor burden in a mouse model of KRAS-driven lung cancer. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization.

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