FOXK1 regulates malignant progression and radiosensitivity through direct transcriptional activation of CDC25A and CDK4 in esophageal squamous cell carcinoma

Abstract

Abstract The transcription factor forkhead box K1 (FOXK1) has recently been recognized to mediate a wide range of biological progresses, including cell proliferation, differentiation, cell cycle progression, apoptosis, DNA damage, and tumorigenesis. However, the role and molecular mechanisms of FOXK1 in esophageal squamous cell carcinoma (ESCC) progression and in the response to ionizing radiation (IR) have not been well characterized. In this study, we investigated the expression level, clinical significance, biological role, and molecular mechanism of FOXK1 in ESCC. High expression level of FOXK1 was observed in ESCC cell lines and tissues, which was correlated with TNM stage, invasion depth, and lymph node metastasis. In addition, overexpression of FOXK1 promoted ESCC cells proliferation, migration, and invasion, whereas silencing FOXK1 showed the opposite effect. Moreover, Silencing FOXK1 enhanced radiosensitivity by inhibiting DNA damage repair, inducing G1 arrest and apoptosis. Further studies revealed that FOXK1 activated transcription of CDC25A and CDK4 in ESCC cells by directly binding to their promoter regions. Furthermore, knockdown of CDC25A or CDK4 reversed those biological processes mediated by overexpression of FOXK1. Collectively, FOXK1, as well as its downstream target genes CDC25A and CDK4, may be potential therapeutic and radiosensitizing targets for ESCC.