Altered Expression of Core Circadian Gene Bmal-1 in Cancer-associated Macrophages

Abstract

Circadian rhythms are endogenous time-keeping machines that allow organisms to anticipate and respond to environmental changes. In the past decade, accumulating evidence has pointed at the direct association between circadian dysfunction and increased prevalence of cancer, as observed in nightshift workers and in individuals with chronic jetlag. Studies on the immune system have deciphered multiple regulatory roles of circadian rhythms. On the other hand, immune cells have also been shown to actively participate in the growth, promotion and invasiveness of cancer. Previous studies on circadian rhythms in macrophages have been limited to exploring the role of circadian genes in activation of inflammation against bacterial endotoxins. While at least 8% of the macrophage transcriptome and many core functions of macrophages, undergo circadian variations, little remains known regarding how circadian genes are expressed in cancer-associated macrophages. Here, we present the first study to characterize macrophage circadian rhythms upon interaction with cancer cells or with specific cytokines. Our data provide evidence that cancer cells could alter circadian rhythms in macrophages. Our results show that upon interaction with cancer, or with cytokine activation, the expression of the master clock gene, Bmal-1 is repressed. Inhibition of Bmal-1 can cause macrophages to remain in an inflammatory state, suggesting that cancer cells can directly disrupt immune homeostasis. Our work therefore has unveiled another dimension in understanding the complexity of the tumor microenvironment, and further suggests a bidirectional tumor-immune crosstalk.