Epigenetic Activation of the KDM6B‐DKK1 Axis Promotes Colorectal Cancer Peritoneal Metastasis Through Wnt/β‐Catenin‐Associated EMT

Abstract

Peritoneal metastasis (PM) is a highly lethal pattern of progression in colorectal cancer (CRC), yet the specific molecular drivers and upstream regulatory mechanisms underlying this process remain incompletely understood. In the present study, public transcriptomic datasets from TCGA and GEO were integrated to identify PM‐associated genes in CRC, and prognostic relevance was evaluated using Kaplan–Meier survival analysis and Cox regression. Stable knockdown and overexpression models were established to investigate the role of DKK1 in CRC cell migration, invasion and peritoneal dissemination using Transwell assays and a mouse peritoneal metastasis model. Multi‐cohort analysis identified 86 genes specifically upregulated in PM, among which DKK1 showed the most consistent overexpression and was significantly associated with poor prognosis in patients with CRC. Functionally, DKK1 knockdown significantly suppressed CRC cell migration, invasion and peritoneal metastatic colonization in vivo, whereas DKK1 overexpression enhanced these malignant phenotypes. Mechanistically, DKK1 promoted metastasis in association with activation of the Wnt/β‐catenin signalling programme and induction of epithelial‐mesenchymal transition. Upstream analysis demonstrated that the histone demethylase KDM6B was positively correlated with DKK1 expression and directly activated DKK1 transcription by binding to its promoter and reducing H3K27me3 enrichment. Rescue experiments further indicated that the pro‐metastatic and epithelial‐mesenchymal transition‐promoting effects of KDM6B were largely dependent on DKK1. Collectively, these findings identify DKK1 as a key driver of CRC PM and establish the KDM6B‐DKK1‐Wnt/β‐catenin‐epithelial‐mesenchymal transition axis as a critical regulatory pathway in this process.