Bmal1-mediated circadian MELK expression potentiates MELK inhibitor chronotherapy for esophageal cancer.

Abstract

Esophageal squamous cell carcinoma (ESCC) remains a global health challenge. Circadian clock and Maternal embryonic leucine zipper kinase (MELK) play a key role in tumorigenesis. However, a link between circadian clock dysregulation and MELK function in the occurrence and development of ESCC remains elusive. Here, In the in vivo and in vitro systems, we found for the first time that MELK exhibits pronounced circadian rhythms expression in mice esophageal tissue, xenograft model and human ESCC cells. The diurnal differences expression between peak (ZT0) and trough (ZT12) points in normal esophageal tissue is nearly 10-fold. Circadian expression of MELK in ESCC cells was regulated by Bmal1 through binding to the MELK promoter. Supporting this, the levels of MELK were increased significantly in ESCC patients, and was accompanied with altered expression of core clock genes, especially, Bmal1 is prominently upregulated. Most importantly, Bmal1-deleted eliminated the rhythmic expression of MELK, while knockdown of other core genes had no effect on MELK expression. Furthermore, in nude mice with transplanted tumor, the anticancer effect of OTS167 at ZT0 administration is twice that of ZT12. Implications: Our findings suggest that MELK represents a therapeutic target, and can as a regulator of circadian control ESCC growth, with these findings advance our understanding of the clinical potential of chronotherapy and the importance of time-based MELK inhibition in cancer treatment.