GSE194097
Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer
Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined.  We demonstrate that exposure to chronic circadian disruption (chronic jetlag, CJL) increases tumor formation in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. 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. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis. Overall design: To identify mechanisms potentially underlying the pro-tumorigenic effect of CJL in K mice, we compared the transcriptional programs in tumors and total lung from K mice housed in normal or CJL conditions. Up to 12 individual tumors were collected from each animal at either ZT9 or ZT21 and the remaining lung tissue was also collected for subsequent analyses. We sequenced RNA prepared from 3 tumors per animal and two mice per time point and lighting condition