HKDC1 promotes colorectal cancer progression by regulating RCOR1 expression to activate the Wnt/β-catenin pathway, enhancing proliferation, migration, and epithelial-mesenchymal transition (EMT).

Abstract

HKDC1 (Hexokinase Domain Containing 1) has been identified as an oncogenic factor in various malignancies. The role and mechanisms of HKDC1 in colorectal cancer (CRC) are not well known. This study aims to investigate the expression pattern of HKDC1 in CRC and its role in tumor growth, migration, glycolysis, and EMT, as well as to elucidate the underlying molecular mechanisms. We analyzed HKDC1 expression across multiple cancers using TIMER2.0 and TCGA databases, and assessed its prognostic value with Kaplan-Meier survival analysis. HKDC1 expression in CRC tissues was validated by Western blotting (WB), immunohistochemistry (IHC), and qRT-PCR, and its correlation with patient prognosis was examined. Functional studies involving HKDC1 knockdown and overexpression were conducted to examine its impact on CRC cell proliferation, migration, cell cycle, apoptosis, and EMT. Co-immunoprecipitation (Co-IP), Immunofluorescence (IF) and mass spectrometry identified HKDC1's interaction with RCOR1, revealing HKDC1's regulation of the Wnt/β-catenin pathway through RCOR1 to promote CRC progression. HKDC1 exhibited high expression levels in CRC tissues and cells, correlating with poor prognosis in CRC patients. Functional assays revealed that HKDC1 knockdown significantly inhibited CRC cell proliferation and migration, induced G1 phase cell cycle arrest, and promoted apoptosis, whereas HKDC1 overexpression produced the opposite effects. HKDC1 modulated EMT and increased glycolysis through the Wnt/β-catenin signaling pathway. HKDC1 knockdown inhibited CRC tumor growth in vivo, whereas its overexpression promoted tumor progression. HKDC1 interacted with RCOR1 to upregulate its expression, activating the Wnt/β-catenin pathway and promoting CRC cell proliferation, migration, and EMT. This study is the first to demonstrate that HKDC1 enhances CRC proliferation, migration, glycolysis, and EMT by modulating RCOR1 and activating the Wnt/β-catenin pathway. HKDC1 could be a therapeutic target and prognostic marker in CRC, providing new insights for personalized treatment.