Lysine demethylase 5B suppresses CC chemokine ligand 14 to promote progression of colorectal cancer through the Wnt/β-catenin pathway

Aims: Epigenetic and genetic alterations are crucial events in the onset and progression of human cancers including colorectal Cancer (CRC). This work aims to probe the relevance of lysine demethylase 5B (KDM5B) to the progression of CRC and the possible molecules involved.

Materials and methods: KDM5B expression in CRC tissues and cells was determined. The association between KDM5B and the prognosis of patients was analyzed. Gain- and loss-of function studies of KDM5B were performed in HT-29 and KDM5B cells to explore the impact of KDM5B on cell behaviors. Expression of CC chemokine ligand 14 (CCL14) in CRC tissues and cells and its correlation with KDM5B were analyzed. Altered expression of CCL14 was introduced in CRC cells, and a Wnt/β-catenin-specific antagonist KYA1797K was induced in cells as well.

Key findings: KDM5B was abundantly expressed while CCL14 was poorly expressed in CRC tissues and cells. High KDM5B expression was relevant to poor prognosis of patients. Downregulation of KDM5B suppressed proliferation and aggressiveness of HT-29 cells, and reduced the growth of xenograft tumors in mice, while upregulation of KDM5B in SW480 cells led to reverse results. KDM5B reduced CCL14 expression through demethylation modification of H3K4me3. Upregulation of CCL14 suppressed colony formation and invasiveness of CRC cells. KDM5B downregulated CCL14 to activate the Wnt/β-catenin. Inhibition of β-catenin by KYA1797K blocked the oncogenic roles of KDM5B in cells and in xenograft tumors.

Significance: This study suggested that KDM5B suppresses CCL14 through demethylation modification of H3K4me3, leading to activation of the Wnt/β-catenin and the CRC progression.