Abstract
Circadian oscillation is an essential process that influences many physiological and biological mechanisms and a decrease of circadian genes is associated with many diseases such as cancer. Despite many efforts to identify the detailed mechanism for decreasing circadian genes and recovering reduced circadian genes in cancer, it is still largely unknown. We found that BMAL1 was reduced in tumor hypoxia-induced acidosis, and recovered by selectively targeting acidic pH in breast cancer cell lines. Surprisingly, BMAL1 was reduced by decrease of protein stability as well as inhibition of transcription under acidosis. In addition, melatonin significantly prevented acidosis-mediated decrease of BMAL1 by inhibiting lactate dehydrogenase-A during hypoxia. Remarkably, acidosis-mediated metastasis was significantly alleviated by BMAL1 overexpression in breast cancer cells. We therefore suggest that tumor hypoxia-induced acidosis promotes metastatic potency by decreasing BMAL1, and that tumor acidosis could be a target for preventing breast cancer metastasis by sustaining BMAL1.
Highlights
Breast cancer is the most common cancer in females worldwide, and the second most cancer-related death reported annually [1,2]
Since previous studies have reported that circadian genes including brain and muscle Arnt-like protein-1 (BMAL1) are reduced in almost cancers, we hypothesized that tumor hypoxia, a common and predominant occurrence in cancer, plays a critical role in decrease of the BMAL1 circadian gene
When Hypoxia-inducible factors (HIFs)-1α was silenced during hypoxia, it did not prevent the decrease of BMAL1 protein expression (Supplementary Figure S1e). These results suggested that BMAL1 was reduced by chronic hypoxia independently of HIF-1α in breast cancer cells
Summary
Breast cancer is the most common cancer in females worldwide, and the second most cancer-related death reported annually [1,2]. Cancer metastasis represents progression of the primary cancer [3,4], with over 80% of breast cancer-related deaths diagnosed with metastasis [5]. A better understanding of cancer and new treatment strategies are needed to prevent metastasis of breast cancer. The circadian clock maintains daily oscillation rhythms with a 24 h periodicity in all living organisms. It responds to stimuli from external environments such as light, which affect pathological and physiological functions [7]. Several genes are associated with the circadian clock, including brain and muscle Arnt-like protein-1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), period (PERs; Per, Per, and Per3), and cryptochromes (CRYs; Cry and Cry2), which form a complex network of transcription–translation feedback loops, post-translational modifications, and degradation [8,9]
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