KDM5D inhibits the transcriptional activation of FKBP4 by suppressing the expression of E2F1 in colorectal cancer in males

Colorectal cancer (CRC) remains the most frequently diagnosed malignancy and also a major contributor to cancer-related death throughout the world. Here, we first revealed the role of histone lysine-specific demethylase 5D (KDM5D) in CRC in males. KDM5D expression in tumor and adjacent tissues of male CRC patients was investigated using immunohistochemistry and RT-qPCR, and the correlation between its expression and patients' prognosis was analyzed. Downregulation of KDM5D in CRC patients was associated with poor prognoses. Overexpression of KDM5D significantly inhibited the growth and metastasis of CRC in vitro and in vivo. The downstream mechanism of KDM5D in CRC was investigated using bioinformatics analysis, and the regulatory relationship was confirmed by ChIP-qPCR and luciferase reporter assays. KDM5D suppressed E2F1 expression by mediating H3K4me3 demethylation. E2F1, highly expressed in CRC, promoted the expression of FKBP4 at the transcriptional level by binding to the FKBP4 promoter. Finally, rescue experiments revealed that overexpression of FKBP4 significantly reversed the inhibitory effect of KDM5D on CRC growth and metastasis. Collectively, KDM5D exerted an anti-tumor and anti-metastatic in CRC through demethylation in E2F1 and suppression of FKBP4 transcription, which might represent a novel target in CRC treatment in male.