MicroRNA let-7i Inhibits Histone Lysine Demethylase KDM5B to Halt Esophageal Cancer Progression

Recent studies have suggested that microRNA let-7i is a tumor suppressor in human cancers, including esophageal cancer, but its underlying mechanism is not yet fully understood. We investigated the role and mechanisms of let-7i in the progression of esophageal cancer. We first showed that let-7i was downregulated in esophageal cancer tissues and cells and then linked its low expression to cancer progression. Bioinformatic analysis predicted KDM5B as a target gene of let-7i, which was confirmed by a dual-luciferase reporter assay. Loss- and gain-of function approaches were adopted to examine the interactions of let-7i, KDM5B, SOX17, and GREB1 in vitro and in vivo. Overexpression of let-7i suppressed esophageal cancer cell proliferation and invasion and promoted apoptosis. Mechanistic investigation showed that let-7i targeted and inhibited KDM5B expression, whereas KDM5B enhanced H3K4me3 at the SOX17 promoter region. Overexpression of let-7i suppressed the expression of GREB1 in esophageal cancer cells by regulating the KDM5B/SOX17 axis in vivo and in vitro. Taken together, our findings reveal the tumor-suppressive properties of let-7i in esophageal cancer in association with an apparent KDM5B-dependent SOX17/GREB1 axis. This study offers a potential prognostic marker and therapeutic target for esophageal cancer.